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1
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Garcia-Diaz A, Moyano-Rodríguez MJ, Garrido-Navas MDC, de Miguel-Perez D, Expósito-Hernández J, Alcázar-Navarrete B, Ortuño F, Landeira D, Romero PJ, Garcia-Moreno A, Lorente JA, Lopez-Hidalgo J, Bayarri-Lara C, Serrano MJ. Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization. Arch Bronconeumol 2025; 61:156-165. [PMID: 39414465 DOI: 10.1016/j.arbres.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common type of lung neoplasm. Despite surgical resection, it has a high relapse rate, accounting for 30-55% of all cases. Next-generation sequencing (NGS) based on a customized gene panel and the analysis of circulating tumor cells (CTCs) can help identify heterogeneity, stratify high-risk patients, and guide treatment decisions. In this descriptive study involving a small prospective cohort, we focus on the phenotypic characterization of CTCs, particularly concerning EZH2 expression (a member of the Polycomb Repression Complex 2), as well as on the mutation profiles of the tissue using a customized gene panel and their association with poor outcomes in NSCLC. METHODS Isolation and characterization of EZH2 on CTCs were evaluated before surgical resection (CTC1) and one month after surgery (CTC2) in resectable NSCLC patients. Targeted NGS was performed using a customized 50-gene panel on tissue samples from a subset of patients. RESULTS 76 patients with resectable NSCLC were recruited. The top mutated genes in the cohort included TP53, FLT1, MUC5AC, EGFR, and NLRP3. Pair of genes that had mutually exclusive mutations was TP53-RIN3, and pairs of genes with co-occurring mutations were CD163-TLR4, FGF10-FOXP2, ADAMTSL3-FLT1, ADAMTSL3-MUC5AC and MUC5AC-NLRP3. CTCs decreased significantly between the two time points CTC1 and CTC2 (p<0.0001), and CTCs+ patients with high EZH2 expression had an 87% increased risk of death (p=0.018). CONCLUSIONS Integrating molecular profiling of tumors and CTC characterization can provide valuable insights into tumor heterogeneity and improve patient stratification for resectable NSCLC.
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Affiliation(s)
- Abel Garcia-Diaz
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | | | - María Del Carmen Garrido-Navas
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | - Diego de Miguel-Perez
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Jose Expósito-Hernández
- IBS Granada, Instituto de Investigacion Biosanitaria de Granada, Granada, Spain; Comprehensive Oncology Division, Virgen de las Nieves University Hospital, Granada, Spain
| | | | - Francisco Ortuño
- Department of Computer Engineering, Automation and Robotics, University of Granada, Granada, Spain
| | - David Landeira
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | - Pedro J Romero
- Department of Medicine School of Medicine, University of Granada, Granada, Spain
| | - Adrian Garcia-Moreno
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | - Jose A Lorente
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain
| | - Javier Lopez-Hidalgo
- IBS Granada, Instituto de Investigacion Biosanitaria de Granada, Granada, Spain; Molecular Pathology Lab, Pathology Service, Virgen de las Nieves University Hospital, Granada, Spain
| | - Clara Bayarri-Lara
- Department of Thoracic Surgery, Virgen de las Nieves University Hospital, Granada, Spain.
| | - Maria Jose Serrano
- GENYO Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, Granada, Spain; IBS Granada, Instituto de Investigacion Biosanitaria de Granada, Granada, Spain; Molecular Pathology Lab, Pathology Service, Virgen de las Nieves University Hospital, Granada, Spain.
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Amaratunga SA, Tayeb TH, Dusatkova P, Elblova L, Drabova J, Plachy L, Pruhova S, Lebl J. High yield of monogenic short stature in children from Kurdistan, Iraq: A genetic testing algorithm for consanguineous families. Genet Med 2025; 27:101332. [PMID: 39580647 DOI: 10.1016/j.gim.2024.101332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024] Open
Abstract
PURPOSE Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
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Affiliation(s)
- Shenali Anne Amaratunga
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Tara Hussein Tayeb
- Department of Paediatrics, Sulaimani University, College of Medicine, Sulaimani, Iraq
| | - Petra Dusatkova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Lenka Elblova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Jana Drabova
- Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Lukas Plachy
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Stepanka Pruhova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Jan Lebl
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
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Méndez-Vidal C, Bravo-Gil N, Pérez-Florido J, Marcos-Luque I, Fernández RM, Fernández-Rueda JL, González-Del Pozo M, Martín-Sánchez M, Fernández-Suárez E, Mena M, Carmona R, Dopazo J, Borrego S, Antiñolo G. A genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice. J Transl Med 2025; 23:86. [PMID: 39833864 PMCID: PMC11748347 DOI: 10.1186/s12967-025-06069-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program. METHODS Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings. RESULTS Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments. CONCLUSION This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.
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Affiliation(s)
- Cristina Méndez-Vidal
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Nereida Bravo-Gil
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Javier Pérez-Florido
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
- Platform of Computational Medicine. Fundación Progreso y Salud (FPS). CDCA, University Hospital Virgen del Rocio, Seville, Spain
| | - Irene Marcos-Luque
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
| | - Raquel M Fernández
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
| | - José Luis Fernández-Rueda
- Platform of Computational Medicine. Fundación Progreso y Salud (FPS). CDCA, University Hospital Virgen del Rocio, Seville, Spain
| | - María González-Del Pozo
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Marta Martín-Sánchez
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Elena Fernández-Suárez
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Marcela Mena
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | - Rosario Carmona
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
- Platform of Computational Medicine. Fundación Progreso y Salud (FPS). CDCA, University Hospital Virgen del Rocio, Seville, Spain
| | - Joaquín Dopazo
- Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
- Platform of Computational Medicine. Fundación Progreso y Salud (FPS). CDCA, University Hospital Virgen del Rocio, Seville, Spain
| | - Salud Borrego
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain.
| | - Guillermo Antiñolo
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville, IBiS/University Hospital Virgen del Rocio, CSIC/University of Seville, Seville, Spain.
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Vernet Machado Bressan Wilke M, Goldstein J, Groopman E, Mohan S, Waddell A, Fernandez R, Chen H, Bali D, Baudet H, Clarke L, Hung C, Mao R, Yuzyuk T, Craigen WJ, Pinto E Vairo F. Developing a scoring system for gene curation prioritization in lysosomal diseases. Mol Genet Metab 2024; 143:108572. [PMID: 39265286 PMCID: PMC11473227 DOI: 10.1016/j.ymgme.2024.108572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/14/2024]
Abstract
INTRODUCTION Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels. METHODS Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into "Overall Definition," "Phenotype," and "Pathophysiology." These criteria included concepts such as the "accumulation of undigested or partially digested macromolecules within the lysosome" and being "associated with a wide spectrum of clinical manifestations impacting multiple organs and systems." The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between "major" and "minor" criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List. RESULTS The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels. DISCUSSION The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP. CONCLUSION The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research.
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Affiliation(s)
| | - Jennifer Goldstein
- University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Emily Groopman
- Children's National Hospital, Washington, DC, United States of America
| | - Shruthi Mohan
- University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Amber Waddell
- University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Raquel Fernandez
- American College of Genetics and Genomics, Bethesda, MD, United States of America
| | - Hongjie Chen
- Prevention Genetics, part of Exact Sciences, Marshfield, WI, United States of America
| | - Deeksha Bali
- Duke University Health System, Durham, NC, United States of America
| | - Heather Baudet
- University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Lorne Clarke
- University of British Columbia, Vancouver, Canada
| | | | - Rong Mao
- ARUP Laboratories, Salt Lake City, UT, United States of America; University of Utah, Salt Lake City, UT, United States of America
| | - Tatiana Yuzyuk
- ARUP Laboratories, Salt Lake City, UT, United States of America; University of Utah, Salt Lake City, UT, United States of America
| | | | - Filippo Pinto E Vairo
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States of America.
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Wilke MVMB, Klee EW, Dhamija R, Fervenza FC, Thomas B, Leung N, Hogan MC, Hager MM, Kolbert KJ, Kemppainen JL, Loftus EC, Leitzen KM, Vitek CR, McAllister T, Lazaridis KN, Pinto E Vairo F. Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases. Orphanet J Rare Dis 2024; 19:216. [PMID: 38790019 PMCID: PMC11127317 DOI: 10.1186/s13023-024-03213-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. RESULTS We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). CONCLUSION ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
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Affiliation(s)
| | - Eric W Klee
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Radhika Dhamija
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
| | | | | | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Marie C Hogan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | | | - Kayla J Kolbert
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Elle C Loftus
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Katie M Leitzen
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Carolyn R Vitek
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Tammy McAllister
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Konstantinos N Lazaridis
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Filippo Pinto E Vairo
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
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Salik D, Marangoni M, Dangoisse C, Richert B, Smits G. Efficiency of clinical exome sequencing in the diagnosis of pediatric genodermatoses: A prospective cohort study. J Am Acad Dermatol 2024; 90:1020-1023. [PMID: 38191074 DOI: 10.1016/j.jaad.2023.12.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/10/2023] [Accepted: 12/19/2023] [Indexed: 01/10/2024]
Affiliation(s)
- Deborah Salik
- Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles (ULB), Brussels, Belgium.
| | - Martina Marangoni
- Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Chantal Dangoisse
- Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
| | - Bertrand Richert
- Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
| | - Guillaume Smits
- Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles (ULB), Brussels, Belgium; Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Université Libre de Bruxelles (ULB), Brussels, Belgium; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles, Brussels, Belgium
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Goljan E, Abouelhoda M, Tahir A, ElKalioby M, Meyer B, Monies D. Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population. Hum Genomics 2024; 18:30. [PMID: 38523294 PMCID: PMC10962151 DOI: 10.1186/s40246-024-00594-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/29/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East. METHODS The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC). RESULTS We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations. CONCLUSIONS The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.
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Affiliation(s)
- Ewa Goljan
- Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Mohammed Abouelhoda
- Computational Biosciences, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Asma Tahir
- Computational Biosciences, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohamed ElKalioby
- Computational Biosciences, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Brian Meyer
- Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Dorota Monies
- Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
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Kunisetty B, Martin-Giacalone BA, Zhao X, Luna PN, Brooks BP, Hufnagel RB, Shaw CA, Rosenfeld JA, Agopian AJ, Lupo PJ, Scott DA. High Clinical Exome Sequencing Diagnostic Rates and Novel Phenotypic Expansions for Nonisolated Microphthalmia, Anophthalmia, and Coloboma. Invest Ophthalmol Vis Sci 2024; 65:25. [PMID: 38502138 PMCID: PMC10959191 DOI: 10.1167/iovs.65.3.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/26/2024] [Indexed: 03/20/2024] Open
Abstract
Purpose A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions. Methods We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC. Results We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes. Conclusions We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.
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Affiliation(s)
- Bhavana Kunisetty
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
| | - Bailey A. Martin-Giacalone
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
| | - Xiaonan Zhao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
- Baylor Genetics, Houston, Texas, United States
| | - Pamela N. Luna
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
| | - Brian P. Brooks
- Ophthalmic Genetics & Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, United States
| | - Robert B. Hufnagel
- Ophthalmic Genetics & Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, United States
| | - Chad A. Shaw
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
| | - Jill A. Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
| | - A. J. Agopian
- Department of Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, Texas, United States
| | - Philip J. Lupo
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
| | - Daryl A. Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States
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9
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Abolhassani A, Fattahi Z, Beheshtian M, Fadaee M, Vazehan R, Ahangari F, Dehdahsi S, Faraji Zonooz M, Parsimehr E, Kalhor Z, Peymani F, Mozaffarpour Nouri M, Babanejad M, Noudehi K, Fatehi F, Zamanian Najafabadi S, Afroozan F, Yazdan H, Bozorgmehr B, Azarkeivan A, Sadat Mahdavi S, Nikuei P, Fatehi F, Jamali P, Ashrafi MR, Karimzadeh P, Habibi H, Kahrizi K, Nafissi S, Kariminejad A, Najmabadi H. Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population. NPJ Genom Med 2024; 9:12. [PMID: 38374194 PMCID: PMC10876633 DOI: 10.1038/s41525-024-00393-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 01/29/2024] [Indexed: 02/21/2024] Open
Abstract
Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.
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Affiliation(s)
- Ayda Abolhassani
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Zohreh Fattahi
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | | | - Mahsa Fadaee
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Raheleh Vazehan
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Fatemeh Ahangari
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Shima Dehdahsi
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | | | - Elham Parsimehr
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Zahra Kalhor
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Fatemeh Peymani
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | | | - Mojgan Babanejad
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Khadijeh Noudehi
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Fatemeh Fatehi
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | | | - Fariba Afroozan
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Hilda Yazdan
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Bita Bozorgmehr
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Azita Azarkeivan
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
| | | | - Pooneh Nikuei
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Nasle Salem Genetic Counseling Center, Bandar Abbas, Iran
| | - Farzad Fatehi
- Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Payman Jamali
- Genetic Counseling Center, Shahroud Welfare Organization, Semnan, Iran
| | | | - Parvaneh Karimzadeh
- Pediatric Neurology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Haleh Habibi
- Hamedan University of Medical Science, Hamedan, Iran
| | - Kimia Kahrizi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Shahriar Nafissi
- Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hossein Najmabadi
- Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran.
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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10
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Derrick CJ, Szenker-Ravi E, Santos-Ledo A, Alqahtani A, Yusof A, Eley L, Coleman AHL, Tohari S, Ng AYJ, Venkatesh B, Alharby E, Mansard L, Bonnet-Dupeyron MN, Roux AF, Vaché C, Roume J, Bouvagnet P, Almontashiri NAM, Henderson DJ, Reversade B, Chaudhry B. Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish. Hum Mol Genet 2024; 33:150-169. [PMID: 37815931 PMCID: PMC10772043 DOI: 10.1093/hmg/ddad171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/11/2023] [Accepted: 09/28/2023] [Indexed: 10/12/2023] Open
Abstract
Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
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Affiliation(s)
- Christopher J Derrick
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | | | - Adrian Santos-Ledo
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Ahlam Alqahtani
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Amirah Yusof
- Genome Institute of Singapore (GIS), A*STAR, 60 Biopolis St, 138672, Singapore
| | - Lorraine Eley
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Alistair H L Coleman
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Sumanty Tohari
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Dr, Proteos, 138673, Singapore
| | - Alvin Yu-Jin Ng
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Dr, Proteos, 138673, Singapore
- MGI Tech Singapore Pte Ltd, 21 Biopolis Rd, 138567, Singapore
| | - Byrappa Venkatesh
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Dr, Proteos, 138673, Singapore
| | - Essa Alharby
- Center for Genetics and Inherited Diseases, Taibah University, 7534 Abdul Muhsin Ibn Abdul Aziz, Al Ihn, Al-Madinah al-Munawwarah 42318, Saudi Arabia
- Faculty of Applied Medical Sciences, Taibah University, Janadah Bin Umayyah Road, Tayba, Al-Madinah al-Munawwarah 42353, Saudi Arabia
| | - Luke Mansard
- Molecular Genetics Laboratory, University of Montpellier, CHU Montpellier, 163 Rue Auguste Broussonnet, 34090 Montpellier, France
- Institute for Neurosciences of Montpellier (INM), University of Montpellier, Inserm, 80 Av. Augustin Fliche, 34000 Montpellier, France
| | | | - Anne-Francoise Roux
- Molecular Genetics Laboratory, University of Montpellier, CHU Montpellier, 163 Rue Auguste Broussonnet, 34090 Montpellier, France
- Institute for Neurosciences of Montpellier (INM), University of Montpellier, Inserm, 80 Av. Augustin Fliche, 34000 Montpellier, France
| | - Christel Vaché
- Molecular Genetics Laboratory, University of Montpellier, CHU Montpellier, 163 Rue Auguste Broussonnet, 34090 Montpellier, France
- Institute for Neurosciences of Montpellier (INM), University of Montpellier, Inserm, 80 Av. Augustin Fliche, 34000 Montpellier, France
| | - Joëlle Roume
- Département de Génétique, CHI Poissy, St Germain-en-Laye, 10 Rue du Champ Gaillard, 78300 Poissy, France
| | - Patrice Bouvagnet
- CPDPN, Hôpital MFME, CHU de Martinique, Fort de France, Fort-de-France 97261, Martinique, France
| | - Naif A M Almontashiri
- Center for Genetics and Inherited Diseases, Taibah University, 7534 Abdul Muhsin Ibn Abdul Aziz, Al Ihn, Al-Madinah al-Munawwarah 42318, Saudi Arabia
- Faculty of Applied Medical Sciences, Taibah University, Janadah Bin Umayyah Road, Tayba, Al-Madinah al-Munawwarah 42353, Saudi Arabia
| | - Deborah J Henderson
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Bruno Reversade
- Genome Institute of Singapore (GIS), A*STAR, 60 Biopolis St, 138672, Singapore
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Dr, Proteos, 138673, Singapore
- Smart-Health Initiative, BESE, KAUST, Thuwal, 23955-6900, Kingdom of Saudi Arabia
- Medical Genetics Department, Koç Hospital Davutpaşa Caddesi 34010 Topkapı Istanbul, Istanbul, Turkey
| | - Bill Chaudhry
- Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
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11
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Yu H, Yu H, Zhang R, Peng D, Yan D, Gu Y, Bao Y, Jia W, Zhang H, Hu C. Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus. J Mol Cell Biol 2023; 15:mjad040. [PMID: 37327085 PMCID: PMC10847719 DOI: 10.1093/jmcb/mjad040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/12/2023] [Accepted: 06/15/2023] [Indexed: 06/18/2023] Open
Abstract
A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
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Affiliation(s)
- Hairong Yu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Haoyong Yu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Danfeng Peng
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Dandan Yan
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yunjuan Gu
- Department of Endocrinology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yuqian Bao
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China
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12
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Abstract
Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."
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Affiliation(s)
| | - Sonali Malhotra
- MGH Weight Center, Massachusetts General Hospital and Harvard Medical School, 50 Staniford Street, Suite 430, Boston, MA 02114, USA; Rhythm Pharmaceuticals, 222 Berkeley Street, 12th Floor, Boston, MA 02116, USA.
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13
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Fellner A, Goldberg Y, Basel-Salmon L. Ordering genetic testing by neurologists: points to consider. J Neurol 2023:10.1007/s00415-023-11758-3. [PMID: 37154893 DOI: 10.1007/s00415-023-11758-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 04/28/2023] [Accepted: 04/29/2023] [Indexed: 05/10/2023]
Abstract
A significant challenge limiting the comprehensive utilization of genomic medicine is the lack of timely access to genetics specialists. Although neurologists see patients for whom genetic testing should be considered, the knowledge regarding the choice of the optimal genetic test for each case and the management of the test results are out of the scope of their everyday practice. In this review, we provide a step-by-step guide for non-geneticist physicians through the decision-making process when ordering diagnostic genetic testing for monogenic neurological diseases and when dealing with their results.
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Affiliation(s)
- Avi Fellner
- The Neurogenetics Clinic, Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
| | - Yael Goldberg
- Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lina Basel-Salmon
- Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Felsenstein Medical Research Center, Tel-Aviv University, Tel-Aviv, Israel
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14
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Lecca M, Pehlivan D, Suñer DH, Weiss K, Coste T, Zweier M, Oktay Y, Danial-Farran N, Rosti V, Bonasoni MP, Malara A, Contrò G, Zuntini R, Pollazzon M, Pascarella R, Neri A, Fusco C, Marafi D, Mitani T, Posey JE, Bayramoglu SE, Gezdirici A, Hernandez-Rodriguez J, Cladera EA, Miravet E, Roldan-Busto J, Ruiz MA, Bauzá CV, Ben-Sira L, Sigaudy S, Begemann A, Unger S, Güngör S, Hiz S, Sonmezler E, Zehavi Y, Jerdev M, Balduini A, Zuffardi O, Horvath R, Lochmüller H, Rauch A, Garavelli L, Tournier-Lasserve E, Spiegel R, Lupski JR, Errichiello E. Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage. Am J Hum Genet 2023; 110:681-690. [PMID: 36996813 PMCID: PMC10119151 DOI: 10.1016/j.ajhg.2023.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/07/2023] [Indexed: 03/31/2023] Open
Abstract
The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."
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Affiliation(s)
- Mauro Lecca
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Davut Pehlivan
- Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
| | - Damià Heine Suñer
- Molecular Diagnostics and Clinical Genetics Unit, Hospital Universitari Son Espases, Palma, Illes Balears, Spain; Genomics of Health, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain
| | - Karin Weiss
- Genetics Institute, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Thibault Coste
- AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France; Université de Paris, INSERM UMR-1141 Neurodiderot, Paris, France
| | - Markus Zweier
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
| | - Yavuz Oktay
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey; Department of Medical Biology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | | | - Vittorio Rosti
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | | | - Alessandro Malara
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; Laboratory of Biochemistry-Biotechnology and Advanced Diagnostics, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Gianluca Contrò
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Roberta Zuntini
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Marzia Pollazzon
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Rosario Pascarella
- Neuroradiology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alberto Neri
- Ophthalmology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Carlo Fusco
- Child Neurology and Psychiatry Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Dana Marafi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait
| | - Tadahiro Mitani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Jennifer Ellen Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Sadik Etka Bayramoglu
- Tertiary ROP Center, Health Science University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey
| | - Alper Gezdirici
- Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey
| | | | - Emilia Amengual Cladera
- Genomics of Health, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain
| | - Elena Miravet
- Metabolic Pathologies and Pediatric Neurology Unit, Pediatric Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain
| | - Jorge Roldan-Busto
- Pediatric Radiology Unit, Radiology Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain
| | - María Angeles Ruiz
- Metabolic Pathologies and Pediatric Neurology Unit, Pediatric Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain
| | - Cristofol Vives Bauzá
- Neurobiology, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain
| | - Liat Ben-Sira
- Department of Radiology, Division of Pediatric Radiology, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Sabine Sigaudy
- AP-HM, Service de Génétique, Hôpital de la Timone, Marseille, France
| | - Anaïs Begemann
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
| | - Sheila Unger
- Medical Genetics Service, CHUV, University of Lausanne, Lausanne, Switzerland
| | - Serdal Güngör
- Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Pediatric Neurology, Malatya, Turkey
| | - Semra Hiz
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey; Department of Pediatric Neurology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Ece Sonmezler
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey
| | - Yoav Zehavi
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics B, Emek Medical Center, Afula, Israel
| | - Michael Jerdev
- Poriya Medical Center and the Azrieli Faculty of Medicine, Bar-Ilan University, Ramat-Gan, Israel
| | - Alessandra Balduini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - Orsetta Zuffardi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Rita Horvath
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PY, UK; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0PY, UK
| | - Hanns Lochmüller
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa ON K1H 8L1, Canada; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 8L1, Canada
| | - Anita Rauch
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland; University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Livia Garavelli
- Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elisabeth Tournier-Lasserve
- AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France; Université de Paris, INSERM UMR-1141 Neurodiderot, Paris, France
| | - Ronen Spiegel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics B, Emek Medical Center, Afula, Israel
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Edoardo Errichiello
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy.
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15
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Perrier S, Guerrero K, Tran LT, Michell-Robinson MA, Legault G, Brais B, Sylvain M, Dorman J, Demos M, Köhler W, Pastinen T, Thiffault I, Bernard G. Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing. Front Neurol 2023; 14:1148377. [PMID: 37077564 PMCID: PMC10108901 DOI: 10.3389/fneur.2023.1148377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/23/2023] [Indexed: 04/05/2023] Open
Abstract
IntroductionRare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.MethodsEach of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.ResultsFollowing different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.DiscussionThis study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies.
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Affiliation(s)
- Stefanie Perrier
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Kether Guerrero
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Luan T. Tran
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Mackenzie A. Michell-Robinson
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Geneviève Legault
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - Bernard Brais
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Michel Sylvain
- Division of Pediatric Neurology, Centre Mère-Enfant Soleil du CHU de Québec - Université Laval, Québec City, QC, Canada
| | - James Dorman
- John H. Stroger Jr. Hospital of Cook County, Chicago, IL, United States
- Department of Neurological Sciences, Rush Medical College, Chicago, IL, United States
| | - Michelle Demos
- Division of Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada
| | - Wolfgang Köhler
- Leukodystrophy Center, University of Leipzig Medical Center, Leipzig, Germany
| | - Tomi Pastinen
- Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States
- University of Missouri Kansas City School of Medicine, Kansas City, MO, United States
| | - Isabelle Thiffault
- Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States
- University of Missouri Kansas City School of Medicine, Kansas City, MO, United States
- Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United States
- Isabelle Thiffault
| | - Geneviève Bernard
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Geneviève Bernard
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16
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Salik D, Richert B, Smits G. Clinical and molecular diagnosis of genodermatoses: Review and perspectives. J Eur Acad Dermatol Venereol 2023; 37:488-500. [PMID: 36502512 DOI: 10.1111/jdv.18769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022]
Abstract
Genodermatoses are a complex and heterogeneous group of genetic skin disorders characterized by variable expression and clinical and genetic heterogeneity, rendering their diagnosis challenging. DNA-based techniques, like whole-exome sequencing, can establish a diagnosis in 50% of cases. RNA-sequencing is emerging as an attractive tool that can obtain information regarding gene expression while integrating functional genomic data with regard to the interpretation of variants. This increases the diagnostic rate by an additional 10-15%. In the present review, we detail the clinical steps involved in the diagnosis of genodermatoses, as well as the current DNA-based technologies available to clinicians. Herein, the intention is to facilitate a better understanding of the possibilities and limitations of these diagnostic technologies. In addition, this review could guide dermatologists through new emerging techniques, such as RNA-sequencing and its applications to familiarizing them with future techniques. Currently, this multi-omics approach is likely the best strategy designed to promote the diagnosis of patients with genodermatoses and discover new skin disease genes that could result in novel targeted therapies.
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Affiliation(s)
- Deborah Salik
- Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
| | - Bertrand Richert
- Department of Dermatology, CHU Saint-Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
| | - Guillaume Smits
- Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles (ULB), Brussels, Belgium.,Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics Université Libre de Bruxelles (ULB), Brussels, Belgium.,Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles, Brussels, Belgium
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17
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Nassar A, Zekri ARN, Kamel MM, Elberry MH, Lotfy MM, Seadawy MG, Hassan ZK, Soliman HK, Lymona AM, Youssef ASED. Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study. Genes (Basel) 2022; 14:106. [PMID: 36672847 PMCID: PMC9858960 DOI: 10.3390/genes14010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/23/2022] [Accepted: 12/08/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Precision oncology has been increasingly used in clinical practice and rapidly evolving in the oncology field. Thus, this study was performed to assess the frequency of germline mutations in early and late onset familial breast cancer (BC) Egyptian patients using multi-gene panel sequencing to better understand the contribution of the inherited germline mutations in BC predisposition. Moreover, to determine the actionable deleterious mutations associated with familial BC that might be used as biomarker for early cancer detection. METHODS Whole blood samples were collected from 101 Egyptian patients selected for BC family history, in addition to 50 age-matched healthy controls. A QIAseq targeted DNA panel (human BC panel) was used to assess the frequency of germline mutations. RESULTS A total of 58 patients (57.4%) out of 101 were found to have 27 deleterious germline mutations in 11 cancer susceptibility genes. Of them, 32 (31.6%) patients carried more than one pathogenic mutation and each one carried at least one pathogenic mutation. The major genes harboring the pathogenic mutations were: ATM, BRCA2, BRCA1, VHL, MSH6, APC, CHEK2, MSH2, MEN1, PALB2, and MUTYH. Thirty-one patients (30.6%) had BRCA2 mutations and twenty (19.8%) had BRCA1 mutations. Our results showed that exon 10 and exon 11 harbored 3 and 5 mutations, respectively, in BRCA1 and BRCA2 genes. Our analysis also revealed that the VHL gene significantly co-occurred with each of the BRCA2 gene (p = 0.003, event ratio 11/21), the MSH2 gene (p = 0.01, 4/10), the CHEK2 gene (p = 0.02, 4/11), and the MSH6 gene (p = 0.04, 4/12). In addition, the APC gene significantly co-occurred with the MSH2 gene (p = 0.01, 3/7). Furthermore, there was a significant mutually exclusive event between the APC gene and the ATM gene (p = 0.04, 1/36). Interestingly, we identified population specific germline mutations in genes showing potentials for targeted therapy to meet the need for incorporating precision oncology into clinical practice. For example, the mutations identified in the ATM, APC, and MSH2 genes. CONCLUSIONS Multi-gene panel sequencing was used to detect the deleterious mutations associated with familial BC, which in turns mitigate the essential need for implementing next generation sequencing technologies in precision oncology to identify cancer predisposing genes. Moreover, identifying DNA repair gene mutations, with focus on non-BRCA genes, might serve as candidates for targeted therapy and will be increasingly used in precision oncology.
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Affiliation(s)
- Auhood Nassar
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Abdel-Rahman N. Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mahmoud M. Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
- Baheya Centre for Early Detection and Treatment of Breast Cancer, Giza 3546211, Egypt
| | - Mostafa H. Elberry
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mai M. Lotfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Mohamed G. Seadawy
- Biological Prevention Department, Chemical Warfare, 4.5 km Suez-Cairo Rd, Almaza, Cairo 11351, Egypt
| | - Zeinab K. Hassan
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Hany K. Soliman
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Ahmed M. Lymona
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Amira Salah El-Din Youssef
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
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18
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Alshengeti A. Eczema herpeticum vs dermatitis herpetiformis as a clue of dedicator of cytokinesis 8 deficiency diagnosis: A case report. World J Clin Cases 2022; 10:10735-10741. [PMID: 36312485 PMCID: PMC9602220 DOI: 10.12998/wjcc.v10.i29.10735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/10/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Dedicator of cytokinesis 8 (DOCK 8) deficiency, also known as autosomal recessive hyper immunoglobulin E (IgE) syndrome, is a combined immunodeficiency disease that was first recognized in 2009. It is caused by genetic alterations (mutations or deletions) in the DOCK 8 gene and is characterized by multiple allergies, elevated IgE levels, and susceptibility to viral and bacterial infections. Early diagnosis is critical to optimize the success of stem cell transplantation.
CASE SUMMARY This study reports the case of a pediatric patient with DOCK 8 deficiency who had negative genetic testing using multiplex primary immunodeficiency (PID) panel and whole-exome sequencing (WES) with a next-generation sequencing method. He presented with chronic diarrhea and was managed as celiac disease based on previous negative workup for immunodeficiency and duodenal biopsy. He developed a generalized vesicular rash which was thought to be dermatitis herpetiformis associated with celiac disease. However, it turned out to be Eczema herpeticum based on positive herpes simplex virus from blood and lesions. The diagnosis was re-evaluated after the child was found to have multiple viral, bacterial, and parasitic co-infections (herpes simplex virus, cytomegalovirus, Epstein-Barr virus, Salmonella, and cryptosporidiosis). Re-evaluation with target gene testing with copy number variation (CNV) analysis and Multiplex Ligation Probe Amplification (MLPA) showed a large homozygous deletion in the DOCK 8 gene, confirming the diagnosis of DOCK 8 deficiency.
CONCLUSION Targeted gene testing with CNV analysis might detect deletions that can be missed by WES for diagnosing patients with PID.
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Affiliation(s)
- Amer Alshengeti
- Department of Pediatrics, College of Medicine, Taibah University; Department of Infection prevention and control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah 41491, Saudi Arabia
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19
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Beaumont RN, Wright CF. Estimating diagnostic noise in panel-based genomic analysis. Genet Med 2022; 24:2042-2050. [PMID: 35920826 DOI: 10.1016/j.gim.2022.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Gene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panel sizes vary, affecting the test's sensitivity and specificity. We investigated the background rate of candidate variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases. METHODS We used the Gene2Phenotype database with the Variant Effect Predictor plugin to identify rare nonsynonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated 5 clinically curated gene panels of varying sizes (50-1700 genes). RESULTS Bigger gene panels resulted in more prioritized variants, varying from an average of approximately 0.3 to 3.5 variants per person. The number of individuals with prioritized variants varied linearly with coding sequence length for monoallelic genes (∼300 individuals per 1000 base pairs) and quadratically for biallelic genes, with notable outliers. CONCLUSION Although large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they frequently prioritize likely benign variants requiring follow up. Most individuals have ≥1 rare nonsynonymous variant in panels containing >500 disease genes. Extreme caution should be applied when interpreting candidate variants, particularly in the absence of relevant phenotypes.
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Affiliation(s)
- Robin N Beaumont
- Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
| | - Caroline F Wright
- Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
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20
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Reis CS, Quental S, Fernandes S, Castedo S, Moura CP. Whole-Exome Sequencing Targeting a Gene Panel for Sensorineural Hearing Loss: The First Portuguese Cohort Study. Cytogenet Genome Res 2022; 162:1-9. [PMID: 35580552 DOI: 10.1159/000523840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/22/2022] [Indexed: 11/19/2022] Open
Abstract
Next-generation sequencing (NGS) technologies revolutionized the molecular diagnosis of sensorineural hearing loss (SNHL) and are now a standard of care. In this study, 71 Portuguese probands with hereditary SNHL were assessed by whole-exome sequencing (WES) targeting a panel of 158 genes related to SNHL, aiming to evaluate the diagnostic yield of this methodological approach and to report the spectrum of variants. Patients with either nonsyndromic or syndromic SNHL were included. Also, patients were previously screened for variants in the GJB2 gene and for duplications/deletions in the GJB6 gene. Causative variants in 11 different genes were identified in 15 (21.1%) out of 71 probands, 5 of which had associated syndromes. In 6 other patients (8.5%), presumptive causative variants were identified in MYO15A, TMIE, TBC1D24, SPMX, GJB3, PCDH15, and CDH23 genes, uncovering a potential case of digenic Usher syndrome. The study was inconclusive in 20 probands (28.2%), in 19 due to lack of segregation analysis and in one due to uncertain phenotype-genotype matching. In the remaining 30 patients (42.3%) no potentially causative variants were identified. The diagnostic yield did not significantly vary according to the age of hearing-impairment onset. As the first study on the application of NGS technologies in SNHL based on a Portuguese cohort, our results may contribute to characterize the spectrum of variants related to SNHL in the Portuguese population. Additionally, the present study provides new insights into the contribution of MYO3A, TECTA, EDNRB, TBC1D24, and GJB3 genes to SNHL. For the significant number of undiagnosed patients, reanalysis of WES data - either for a broader gene panel or in a non-targeted approach - may be considered.
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Affiliation(s)
| | - Sofia Quental
- IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Institute for Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Susana Fernandes
- Institute for Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal.,Genetics, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Sérgio Castedo
- IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Institute for Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal.,Genetics, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Carla Pinto Moura
- Institute for Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal.,Genetics, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Otorhinolaryngology, University Hospital Center of São João, EPE, Porto, Portugal
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Barbosa-Gouveia S, Vázquez-Mosquera ME, González-Vioque E, Hermida-Ameijeiras Á, Sánchez-Pintos P, de Castro MJ, León SR, Gil-Fournier B, Domínguez-González C, Camacho Salas A, Negrão L, Fineza I, Laranjeira F, Couce ML. Rapid Molecular Diagnosis of Genetically Inherited Neuromuscular Disorders Using Next-Generation Sequencing Technologies. J Clin Med 2022; 11:jcm11102750. [PMID: 35628876 PMCID: PMC9143479 DOI: 10.3390/jcm11102750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/13/2022] [Accepted: 05/09/2022] [Indexed: 02/07/2023] Open
Abstract
Neuromuscular diseases are genetically highly heterogeneous, and differential diagnosis can be challenging. Over a 3-year period, we prospectively analyzed 268 pediatric and adult patients with a suspected diagnosis of inherited neuromuscular disorder (INMD) using comprehensive gene-panel analysis and next-generation sequencing. The rate of diagnosis increased exponentially with the addition of genes to successive versions of the INMD panel, from 31% for the first iteration (278 genes) to 40% for the last (324 genes). The global mean diagnostic rate was 36% (97/268 patients), with a diagnostic turnaround time of 4–6 weeks. Most diagnoses corresponded to muscular dystrophies/myopathies (68.37%) and peripheral nerve diseases (22.45%). The most common causative genes, TTN, RYR1, and ANO5, accounted for almost 30% of the diagnosed cases. Finally, we evaluated the utility of the differential diagnosis tool Phenomizer, which established a correlation between the phenotype and molecular findings in 21% of the diagnosed patients. In summary, comprehensive gene-panel analysis of all genes implicated in neuromuscular diseases facilitates a rapid diagnosis and provides a high diagnostic yield.
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Affiliation(s)
- Sofia Barbosa-Gouveia
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
- Correspondence: (S.B.-G.); (M.L.C.); Tel.: +34-981-950-151 (M.L.C.)
| | - Maria Eugenia Vázquez-Mosquera
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
| | - Emiliano González-Vioque
- Department of Clinical Biochemistry, Puerta de Hierro-Majadahonda University Hospital, 28222 Majadahonda, Spain;
| | - Álvaro Hermida-Ameijeiras
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
| | - Paula Sánchez-Pintos
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
| | - Maria José de Castro
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
| | - Soraya Ramiro León
- Genetics Department, Hospital Universitario de Getafe, 28905 Madrid, Spain; (S.R.L.); (B.G.-F.)
| | - Belén Gil-Fournier
- Genetics Department, Hospital Universitario de Getafe, 28905 Madrid, Spain; (S.R.L.); (B.G.-F.)
| | - Cristina Domínguez-González
- Neuromuscular Unit, Imas12 Research Institute, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;
- Center for Biomedical Network Research On Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ana Camacho Salas
- Pediatric Neurology Unit, Hospital Universitario 12 de Octubre, Complutense University of Madrid, 28041 Madrid, Spain;
| | - Luis Negrão
- Neuromuscular Diseases Unit, Neurology Service, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal;
| | - Isabel Fineza
- Pediatric Neurology Department, Child Developmental Center, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra Coimbra Portugal, 3000-075 Coimbra, Portugal;
| | - Francisco Laranjeira
- Biochemical Genetics Unit, Centro de Genética Médica Doutor Jacinto Magalhães, 4050-466 Porto, Portugal;
| | - Maria Luz Couce
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, Santiago de Compostela University Clinical Hospital, 15704 Santiago de Compostela, Spain; (M.E.V.-M.); (Á.H.-A.); (P.S.-P.); (M.J.d.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IDIS-Health Research Institute of Santiago de Compostela, Santiago de Compostela University Clinical Hospital, European Reference Network for Hereditary Metabolic Disorders (MetabERN), 15704 Santiago de Compostela, Spain
- Correspondence: (S.B.-G.); (M.L.C.); Tel.: +34-981-950-151 (M.L.C.)
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Liu S, Zeng Y, Wang C, Zhang Q, Chen M, Wang X, Wang L, Lu Y, Guo H, Bu F. seGMM: A New Tool for Gender Determination From Massively Parallel Sequencing Data. Front Genet 2022; 13:850804. [PMID: 35309142 PMCID: PMC8930203 DOI: 10.3389/fgene.2022.850804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 02/10/2022] [Indexed: 11/18/2022] Open
Abstract
In clinical genetic testing, checking the concordance between self-reported gender and genotype-inferred gender from genomic data is a significant quality control measure because mismatched gender due to sex chromosomal abnormalities or misregistration of clinical information can significantly affect molecular diagnosis and treatment decisions. Targeted gene sequencing (TGS) is widely recommended as a first-tier diagnostic step in clinical genetic testing. However, the existing gender-inference tools are optimized for whole genome and whole exome data and are not adequate and accurate for analyzing TGS data. In this study, we validated a new gender-inference tool, seGMM, which uses unsupervised clustering (Gaussian mixture model) to determine the gender of a sample. The seGMM tool can also identify sex chromosomal abnormalities in samples by aligning the sequencing reads from the genotype data. The seGMM tool consistently demonstrated >99% gender-inference accuracy in a publicly available 1,000-gene panel dataset from the 1,000 Genomes project, an in-house 785 hearing loss gene panel dataset of 16,387 samples, and a 187 autism risk gene panel dataset from the Autism Clinical and Genetic Resources in China (ACGC) database. The performance and accuracy of seGMM was significantly higher for the targeted gene sequencing (TGS), whole exome sequencing (WES), and whole genome sequencing (WGS) datasets compared to the other existing gender-inference tools such as PLINK, seXY, and XYalign. The results of seGMM were confirmed by the short tandem repeat analysis of the sex chromosome marker gene, amelogenin. Furthermore, our data showed that seGMM accurately identified sex chromosomal abnormalities in the samples. In conclusion, the seGMM tool shows great potential in clinical genetics by determining the sex chromosomal karyotypes of samples from massively parallel sequencing data with high accuracy.
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Affiliation(s)
- Sihan Liu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yuanyuan Zeng
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China
| | - Chao Wang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Qian Zhang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Meilin Chen
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaolu Wang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lanchen Wang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yu Lu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Yu Lu, ; Hui Guo, ; Fengxiao Bu,
| | - Hui Guo
- Center for Medical Genetics and Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
- *Correspondence: Yu Lu, ; Hui Guo, ; Fengxiao Bu,
| | - Fengxiao Bu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Yu Lu, ; Hui Guo, ; Fengxiao Bu,
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23
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Identification of pharmacogenetic variants from large scale next generation sequencing data in the Saudi population. PLoS One 2022; 17:e0263137. [PMID: 35089958 PMCID: PMC8797234 DOI: 10.1371/journal.pone.0263137] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 01/12/2022] [Indexed: 11/19/2022] Open
Abstract
It is well documented that drug responses are related to Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics of individual patients. Several studies have identified genetic variability in pharmacogenes, that are either directly responsible for or are associated with ADME, giving rise to individualized treatments. Our objective was to provide a comprehensive overview of pharmacogenetic variation in the Saudi population. We mined next generation sequencing (NGS) data from 11,889 unrelated Saudi nationals, to determine the presence and frequencies of known functional SNP variants in 8 clinically relevant pharmacogenes (CYP2C9, CYP2C19, CYP3A5, CYP4F2, VKORC1, DPYD, TPMT and NUDT15), recommended by the Clinical Pharmacogenetics Implementation Consortium (CPIC), and collectively identified 82 such star alleles. Functionally significant pharmacogenetic variants were prevalent especially in CYP genes (excluding CYP3A5), with 10-44.4% of variants predicted to be inactive or to have decreased activity. In CYP3A5, inactive alleles (87.5%) were the most common. Only 1.8%, 0.7% and 0.7% of NUDT15, TPMT and DPYD variants respectively, were predicted to affect gene activity. In contrast, VKORC1 was found functionally, to be highly polymorphic with 53.7% of Saudi individuals harboring variants predicted to result in decreased activity and 31.3% having variants leading to increased metabolic activity. Furthermore, among the 8 pharmacogenes studied, we detected six rare variants with an aggregated frequency of 1.1%, that among several other ethnicities, were uniquely found in Saudi population. Similarly, within our cohort, the 8 pharmacogenes yielded forty-six novel variants predicted to be deleterious. Based upon our findings, 99.2% of individuals from the Saudi population carry at least one actionable pharmacogenetic variant.
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24
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Alharbi N, Matar R, Cupler E, Al-Hindi H, Murad H, Alhomud I, Monies D, Alshehri A, Alyahya M, Meyer B, Bohlega S. Clinical, Neurophysiological, Radiological, Pathological, and Genetic Features of Dysferlinopathy in Saudi Arabia. Front Neurosci 2022; 16:815556. [PMID: 35273475 PMCID: PMC8902167 DOI: 10.3389/fnins.2022.815556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundTo characterize the phenotypic, neurophysiological, radiological, pathological, and genetic profile of 33 Saudi Arabian families with dysferlinopathy.MethodsA descriptive observational study was done on a cohort of 112 Saudi Arabian families with LGMD. Screening for the Dysferlin (DYSF) gene was done in a tertiary care referral hospital in Saudi Arabia. Clinical, Neurophysiological, Radiological, Pathological, and Genetic findings in subjects with dysferlin mutation were the primary outcome variables. Statistical analysis was done by Epi-info.Results33 out of 112 families (29.46%) registered in the LGMD cohort had Dysferlinopathy. 53 subjects (28 males, 52.83%) from 33 families were followed up for various periods ranging from 1 to 28 years. The mean age of onset was 17.79 ± 3.48 years (Range 10 to 25 years). Miyoshi Myopathy phenotype was observed in 50.94% (27 out of 53), LGMDR2 phenotype in 30.19% (16 out of 53), and proximodistal phenotype in 15.09% (8 out of 53) of the subjects. Loss of ambulation was observed in 39.62% (21 out of 53 subjects). Electrophysiological, Radiological, and histopathological changes were compatible with the diagnosis. Mean serum Creatinine Kinase was 6,464.45 ± 4,149.24 with a range from 302 to 21,483 IU/L. In addition, 13 dysferlin mutations were identified two of them were compound heterozygous. One founder mutation was observed c.164_165insA in 19 unrelated families.ConclusionThe prevalence of Dysferlinopathy was 29.46% in the native Saudi LGMD cohort. It is the most prevalent subtype seconded by calpainopathy. The clinical course varied among the study subjects and was consistent with those reported from different ethnic groups. One founder mutation was identified. Initial screening of the founder mutations in new families is highly recommended.
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Affiliation(s)
- Norah Alharbi
- Department of Clinical Science, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | - Edward Cupler
- Department of Neuroscience, King Faisal Specialist Hospital, and Research Center, Jeddah, Saudi Arabia
| | - Hindi Al-Hindi
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hatem Murad
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Iftteah Alhomud
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Dorota Monies
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ali Alshehri
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mossaed Alyahya
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Brian Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Saeed Bohlega
- Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- *Correspondence: Saeed Bohlega,
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25
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Nannapaneni H, Ghaleb S, Arya S, Gajula V, Taylor MB, Das BB. Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy. J Cardiovasc Dev Dis 2022; 9:jcdd9030065. [PMID: 35323613 PMCID: PMC8955827 DOI: 10.3390/jcdd9030065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/31/2022] [Accepted: 02/17/2022] [Indexed: 01/27/2023] Open
Abstract
Neonatal dilated cardiomyopathy (DCM) is rare with high etiologic heterogeneity. Recently, biallelic, autosomal recessive, pathogenic variants in RPL3L (ribosomal protein L3-like) have been reported in the literature with severe early-onset DCM. In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp)). Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM. This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis.
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Affiliation(s)
| | - Stephanie Ghaleb
- Department of Pediatrics, Division of Pediatric Cardiology, Children’s of Mississippi Heart Center, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Sandeep Arya
- Department of Pediatrics, Division of Critical Care, Children’s of Mississippi Heart Center, University of Mississippi Medical Center, Jackson, MS 39216, USA; (S.A.); (V.G.); (M.B.T.)
| | - Viswanath Gajula
- Department of Pediatrics, Division of Critical Care, Children’s of Mississippi Heart Center, University of Mississippi Medical Center, Jackson, MS 39216, USA; (S.A.); (V.G.); (M.B.T.)
| | - Mary B. Taylor
- Department of Pediatrics, Division of Critical Care, Children’s of Mississippi Heart Center, University of Mississippi Medical Center, Jackson, MS 39216, USA; (S.A.); (V.G.); (M.B.T.)
| | - Bibhuti B. Das
- Department of Pediatrics, Division of Pediatric Cardiology, Children’s of Mississippi Heart Center, University of Mississippi Medical Center, Jackson, MS 39216, USA;
- Correspondence: ; Tel.: +1-601-984-5250; Fax: +1-601-984-5283
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26
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Romero R, de la Fuente L, Del Pozo-Valero M, Riveiro-Álvarez R, Trujillo-Tiebas MJ, Martín-Mérida I, Ávila-Fernández A, Iancu IF, Perea-Romero I, Núñez-Moreno G, Damián A, Rodilla C, Almoguera B, Cortón M, Ayuso C, Mínguez P. An evaluation of pipelines for DNA variant detection can guide a reanalysis protocol to increase the diagnostic ratio of genetic diseases. NPJ Genom Med 2022; 7:7. [PMID: 35087072 PMCID: PMC8795168 DOI: 10.1038/s41525-021-00278-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 12/09/2021] [Indexed: 01/01/2023] Open
Abstract
Clinical exome (CE) sequencing has become a first-tier diagnostic test for hereditary diseases; however, its diagnostic rate is around 30-50%. In this study, we aimed to increase the diagnostic yield of CE using a custom reanalysis algorithm. Sequencing data were available for three cohorts using two commercial protocols applied as part of the diagnostic process. Using these cohorts, we compared the performance of general and clinically relevant variant calling and the efficacy of an in-house bioinformatic protocol (FJD-pipeline) in detecting causal variants as compared to commercial protocols. On the whole, the FJD-pipeline detected 99.74% of the causal variants identified by the commercial protocol in previously solved cases. In the unsolved cases, FJD-pipeline detects more INDELs and non-exonic variants, and is able to increase the diagnostic yield in 2.5% and 3.2% in the re-analysis of 78 cancer and 62 cardiovascular cases. These results were considered to design a reanalysis, filtering and prioritization algorithm that was tested by reassessing 68 inconclusive cases of monoallelic autosomal recessive retinal dystrophies increasing the diagnosis by 4.4%. In conclusion, a guided NGS reanalysis of unsolved cases increases the diagnostic yield in genetic disorders, making it a useful diagnostic tool in medical genetics.
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Affiliation(s)
- Raquel Romero
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Lorena de la Fuente
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Bioinformatics Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
| | - Marta Del Pozo-Valero
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa Riveiro-Álvarez
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - María José Trujillo-Tiebas
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Inmaculada Martín-Mérida
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Almudena Ávila-Fernández
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Ionut-Florin Iancu
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Perea-Romero
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Gonzalo Núñez-Moreno
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Bioinformatics Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
| | - Alejandra Damián
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Rodilla
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
| | - Berta Almoguera
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Cortón
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Ayuso
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
| | - Pablo Mínguez
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- Bioinformatics Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
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27
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Norton ME, Ziffle JV, Lianoglou BR, Hodoglugil U, Devine WP, Sparks TN. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis. Am J Obstet Gynecol 2022; 226:128.e1-128.e11. [PMID: 34331894 PMCID: PMC8748274 DOI: 10.1016/j.ajog.2021.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/28/2021] [Accepted: 07/22/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Next-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known. OBJECTIVE We compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis. STUDY DESIGN This was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes. RESULTS Exome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing. CONCLUSION The broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.
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Affiliation(s)
- Mary E Norton
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA; Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
| | - Jessica Van Ziffle
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA; Department of Pathology, University of California, San Francisco, San Francisco, CA; Genomic Medicine Laboratory, University of California, San Francisco, San Francisco, CA
| | - Billie R Lianoglou
- Fetal Treatment Center, University of California, San Francisco, San Francisco, CA
| | - Ugur Hodoglugil
- Genomic Medicine Laboratory, University of California, San Francisco, San Francisco, CA
| | - W Patrick Devine
- Department of Pathology, University of California, San Francisco, San Francisco, CA; Genomic Medicine Laboratory, University of California, San Francisco, San Francisco, CA
| | - Teresa N Sparks
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA; Fetal Treatment Center, University of California, San Francisco, San Francisco, CA
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28
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Borgio JF. Heterogeneity in biomarkers, mitogenome and genetic disorders of the Arab population with special emphasis on large-scale whole-exome sequencing. Arch Med Sci 2021; 19:765-783. [PMID: 37313193 PMCID: PMC10259412 DOI: 10.5114/aoms/145370] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/27/2021] [Indexed: 09/20/2024] Open
Abstract
More than 25 million DNA variations have been discovered as novel including major alleles from the Arab population. Exome studies on the Saudi genome discovered > 3000 novel nucleotide variants associated with > 1200 rare genetic disorders. Reclassification of many pathogenic variants in the Human Gene Mutation Database and ClinVar Database as benign through the Arab database facilitates building a detailed and comprehensive map of the human morbid genome. Intellectual disability comes first with the combined and observed carrier frequency of 0.06779 among Saudi Arabians; retinal dystrophy is the next highest. Genome studies have discovered interesting novel candidate disease marker variations in many genes from consanguineous families. More than 7 pathogenic variants in the C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment in Arab ancestries. Advances in large-scale genome studies open a new outlook on Mendelian genes and disorders. In the past half-dozen years, candidate genes of intellectual disability, neurogenetic disorders, blood and bleeding disorders and rare genetic diseases have been well documented through genomic medicine studies in combination with advanced computational biology applications. The Arab mitogenome exposed hundreds of variations in the mtDNA genome and ancestral sharing with Africa, the Near East and East Asia and its association with obesity. These recent discoveries in disease markers and molecular genetics of the Arab population will have a positive impact towards supporting genetic counsellors on reaching consanguineous families to manage stress linked to genetics and precision medicine. This narrative review summarizes the advances in molecular medical genetics and recent discoveries on pathogenic variants. Despite the fact that these initiatives are targeting the genetics and genomics of disorders prevalent in Arab populations, a lack of complete cooperation across the projects needed to be revisited to uncover the Arab population's prominent disease markers. This shows that further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.
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Affiliation(s)
- J Francis Borgio
- Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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29
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Clinical profile and multidisciplinary needs of patients with neuromuscular disorders transitioning from paediatric to adult care. Neuromuscul Disord 2021; 32:206-212. [DOI: 10.1016/j.nmd.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 09/19/2021] [Accepted: 12/08/2021] [Indexed: 11/15/2022]
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30
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Tangaro MA, Mandreoli P, Chiara M, Donvito G, Antonacci M, Parisi A, Bianco A, Romano A, Bianchi DM, Cangelosi D, Uva P, Molineris I, Nosi V, Calogero RA, Alessandri L, Pedrini E, Mordenti M, Bonetti E, Sangiorgi L, Pesole G, Zambelli F. Laniakea@ReCaS: exploring the potential of customisable Galaxy on-demand instances as a cloud-based service. BMC Bioinformatics 2021; 22:544. [PMID: 34749633 PMCID: PMC8574934 DOI: 10.1186/s12859-021-04401-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 09/24/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Improving the availability and usability of data and analytical tools is a critical precondition for further advancing modern biological and biomedical research. For instance, one of the many ramifications of the COVID-19 global pandemic has been to make even more evident the importance of having bioinformatics tools and data readily actionable by researchers through convenient access points and supported by adequate IT infrastructures. One of the most successful efforts in improving the availability and usability of bioinformatics tools and data is represented by the Galaxy workflow manager and its thriving community. In 2020 we introduced Laniakea, a software platform conceived to streamline the configuration and deployment of "on-demand" Galaxy instances over the cloud. By facilitating the set-up and configuration of Galaxy web servers, Laniakea provides researchers with a powerful and highly customisable platform for executing complex bioinformatics analyses. The system can be accessed through a dedicated and user-friendly web interface that allows the Galaxy web server's initial configuration and deployment. RESULTS "Laniakea@ReCaS", the first instance of a Laniakea-based service, is managed by ELIXIR-IT and was officially launched in February 2020, after about one year of development and testing that involved several users. Researchers can request access to Laniakea@ReCaS through an open-ended call for use-cases. Ten project proposals have been accepted since then, totalling 18 Galaxy on-demand virtual servers that employ ~ 100 CPUs, ~ 250 GB of RAM and ~ 5 TB of storage and serve several different communities and purposes. Herein, we present eight use cases demonstrating the versatility of the platform. CONCLUSIONS During this first year of activity, the Laniakea-based service emerged as a flexible platform that facilitated the rapid development of bioinformatics tools, the efficient delivery of training activities, and the provision of public bioinformatics services in different settings, including food safety and clinical research. Laniakea@ReCaS provides a proof of concept of how enabling access to appropriate, reliable IT resources and ready-to-use bioinformatics tools can considerably streamline researchers' work.
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Affiliation(s)
- Marco Antonio Tangaro
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via Giovanni Amendola 122/O, 70126, Bari, Italy
- National Institute for Nuclear Physics (INFN), Section of Bari, Via Orabona 4, 70126, Bari, Italy
| | - Pietro Mandreoli
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via Giovanni Amendola 122/O, 70126, Bari, Italy
- Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milano, Italy
| | - Matteo Chiara
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via Giovanni Amendola 122/O, 70126, Bari, Italy
- Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milano, Italy
| | - Giacinto Donvito
- National Institute for Nuclear Physics (INFN), Section of Bari, Via Orabona 4, 70126, Bari, Italy
| | - Marica Antonacci
- National Institute for Nuclear Physics (INFN), Section of Bari, Via Orabona 4, 70126, Bari, Italy
| | - Antonio Parisi
- Istituto Zooprofilattico Sperimentale Della Puglia e Della Basilicata, Via Manfredonia 20, 71121, Foggia, Italy
| | - Angelica Bianco
- Istituto Zooprofilattico Sperimentale Della Puglia e Della Basilicata, Via Manfredonia 20, 71121, Foggia, Italy
| | - Angelo Romano
- National Reference Laboratory for Coagulase-Positive Staphylococci Including Staphylococcus Aureus, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, Italy
| | - Daniela Manila Bianchi
- National Reference Laboratory for Coagulase-Positive Staphylococci Including Staphylococcus Aureus, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, Italy
| | - Davide Cangelosi
- Clinical Bioinformatics Unit, Scientific Direction, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147, Genova, Italy
| | - Paolo Uva
- Clinical Bioinformatics Unit, Scientific Direction, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147, Genova, Italy
- Italian Institute of Technology, Via Morego 30, 16163, Genova, Italy
| | - Ivan Molineris
- Department of Life Science and System Biology, University of Turin, Via Accademia Albertina, 13-1023, Turin, Italy
| | - Vladimir Nosi
- Department of Computer Science, University of Turin, Via Pessinetto 12, 10049, Turin, Italy
| | - Raffaele A Calogero
- Department of Molecular Biotechnology and Health Sciences, Via Nizza 52, 10126, Turin, Italy
| | - Luca Alessandri
- Department of Molecular Biotechnology and Health Sciences, Via Nizza 52, 10126, Turin, Italy
| | - Elena Pedrini
- Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy
| | - Marina Mordenti
- Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy
| | - Emanuele Bonetti
- Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139, Milan, Italy
| | - Luca Sangiorgi
- Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via Giovanni Amendola 122/O, 70126, Bari, Italy.
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70126, Bari, Italy.
| | - Federico Zambelli
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via Giovanni Amendola 122/O, 70126, Bari, Italy.
- Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milano, Italy.
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Genetic Insights into the Middle East Respiratory Syndrome Coronavirus Infection among Saudi People. Vaccines (Basel) 2021; 9:vaccines9101193. [PMID: 34696302 PMCID: PMC8539242 DOI: 10.3390/vaccines9101193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/09/2021] [Accepted: 10/13/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The Middle East respiratory syndrome coronavirus (MERS-CoV) was isolated for the first time in Saudi Arabia from a patient suffering from atypical pneumonia. The Saudi Genome database was built by King Abdulaziz Medical City via the next-generation sequencing of 7000 candidates. METHOD A large list of point mutations were reported in the region of the dipeptidyl peptidase 4 (DPP4) gene. The DPP4 amino acid residues correlated to MERS-CoV entry and the site of activity of DPP4 inhibitors was investigated. We retrieved the SNPs (Single-Nucleotide Polymorphism) with a variation frequency of >0.05. RESULTS SNP 2:162,890,175 and SNP 2:162,891,848 in the intronic region were located within 50 bp of amino acid residues responsible for MERS-CoV entry, amino acids 259-296 and 205-258, respectively. The variation frequency of SNP 2:162,890,175 was 2321 out of 2379 screened individuals. Moreover, mutation of SNP 2:162,891,848, which is located near amino acid residues E205 and E206 (crucial for the activity of DPP4 inhibitors), occurred in 76 out of 2379 screened individuals. CONCLUSIONS Our study shows high variation frequency in the DPP4 region reported in the Saudi Genome database. The identified SNPs are of high significance for MERS-CoV infection in better understanding disease pathogenesis.
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Nisar H, Wajid B, Shahid S, Anwar F, Wajid I, Khatoon A, Sattar MU, Sadaf S. Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases. Exp Biol Med (Maywood) 2021; 246:2610-2617. [PMID: 34521224 DOI: 10.1177/15353702211040046] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Rare diseases affect nearly 300 million people globally with most patients aged five or less. Traditional diagnostic approaches have provided much of the diagnosis; however, there are limitations. For instance, simply inadequate and untimely diagnosis adversely affects both the patient and their families. This review advocates the use of whole genome sequencing in clinical settings for diagnosis of rare genetic diseases by showcasing five case studies. These examples specifically describe the utilization of whole genome sequencing, which helped in providing relief to patients via correct diagnosis followed by use of precision medicine.
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Affiliation(s)
- Haseeb Nisar
- Office of Research, Innovation and Commercialization, University of Management and Technology, Lahore 54000, Pakistan.,School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
| | - Bilal Wajid
- Department of Electrical Engineering, University of Engineering and Technology, Lahore 54000, Pakistan.,Ibn Sina Research & Development Division, Sabz-Qalam, Lahore 54000, Pakistan.,Department of Computer Sciences, University of Management and Technology, Lahore 54000, Pakistan
| | - Samiah Shahid
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan
| | - Faria Anwar
- Out Patient Department, Mayo Hospital, Lahore 54000, Pakistan
| | - Imran Wajid
- Ibn Sina Research & Development Division, Sabz-Qalam, Lahore 54000, Pakistan
| | - Asia Khatoon
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
| | - Mian Usman Sattar
- Institute of Social Sciences, Istanbul Commerce University, Istanbul, Turkey
| | - Saima Sadaf
- School of Biochemistry & Biotechnology, University of the Punjab, Lahore 54000, Pakistan
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33
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Zha C, Farah CA, Holt RJ, Ceroni F, Al-Abdi L, Thuriot F, Khan AO, Helaby R, Lévesque S, Alkuraya FS, Kraus A, Ragge NK, Sossin WS. Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits. Hum Mol Genet 2021; 29:3054-3063. [PMID: 32885237 DOI: 10.1093/hmg/ddaa198] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/30/2020] [Accepted: 09/01/2020] [Indexed: 12/11/2022] Open
Abstract
Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.
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Affiliation(s)
- Congyao Zha
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Carole A Farah
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
| | - Richard J Holt
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK
| | - Fabiola Ceroni
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK
| | - Lama Al-Abdi
- Department of Zoology, College of Science, King Saud University, Riyadh 11564, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia
| | - Fanny Thuriot
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Canada
| | - Arif O Khan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.,Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.,Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine at Case Western University, Cleveland, Ohio 44195, USA
| | - Rana Helaby
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia
| | - Sébastien Lévesque
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Canada
| | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11564, Saudi Arabia
| | - Alison Kraus
- Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK
| | - Nicola K Ragge
- Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.,Department of Clinical Genetics, West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Foundation Trust, Birmingham B15 2TG, UK
| | - Wayne S Sossin
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
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34
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Powell L, Olinger E, Wedderburn S, Ramakumaran VS, Kini U, Clayton-Smith J, Ramsden SC, Rice SJ, Barroso-Gil M, Wilson I, Cowley L, Johnson S, Harris E, Montgomery T, Bertoli M, Boltshauser E, Sayer JA. Identification of LAMA1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome. Brain Commun 2021; 3:fcab163. [PMID: 34423300 PMCID: PMC8374969 DOI: 10.1093/braincomms/fcab163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/22/2021] [Accepted: 05/27/2021] [Indexed: 01/17/2023] Open
Abstract
Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.
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Affiliation(s)
- Laura Powell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Eric Olinger
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | | | | | - Usha Kini
- Clinical Genetics, Oxford University Hospital, Oxford, UK
| | - Jill Clayton-Smith
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK
| | - Simon C Ramsden
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK
| | - Sarah J Rice
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Miguel Barroso-Gil
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Ian Wilson
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Lorraine Cowley
- Clinical Genetics, Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Sally Johnson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Elizabeth Harris
- Clinical Genetics, Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Tara Montgomery
- Clinical Genetics, Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | - Marta Bertoli
- Clinical Genetics, Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
| | | | - Eugen Boltshauser
- Paediatric Neurology (Emeritus), Children's University Hospital, Zürich, Switzerland
| | - John A Sayer
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
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35
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Abouelhoda M, Mohty D, Alayary I, Meyer BF, Arold ST, Fadel BM, Monies D. Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining. Hum Genomics 2021; 15:52. [PMID: 34380564 PMCID: PMC8359098 DOI: 10.1186/s40246-021-00351-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/08/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly. RESULTS Three TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis. CONCLUSION Multiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.
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Affiliation(s)
- Mohamed Abouelhoda
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Dania Mohty
- Heart Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
- Al-Faisal University, College of Medicine, Affiliate Harvard Medical School International, Riyadh, Saudi Arabia
| | | | - Brian F Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Stefan T Arold
- Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Bahaa M Fadel
- Heart Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
- Al-Faisal University, College of Medicine, Affiliate Harvard Medical School International, Riyadh, Saudi Arabia
| | - Dorota Monies
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
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Al Qahtani NH, AbdulAzeez S, Almandil NB, Fahad Alhur N, Alsuwat HS, Al Taifi HA, Al-Ghamdi AA, Rabindran Jermy B, Abouelhoda M, Subhani S, Al Asoom L, Borgio JF. Whole-Genome Sequencing Reveals Exonic Variation of ASIC5 Gene Results in Recurrent Pregnancy Loss. Front Med (Lausanne) 2021; 8:699672. [PMID: 34395479 PMCID: PMC8363113 DOI: 10.3389/fmed.2021.699672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/21/2021] [Indexed: 12/08/2022] Open
Abstract
Family trio next-generation sequencing-based variant analysis was done to identify the genomic reason on unexplained recurrent pregnancy loss (RPL). A family (dead fetus and parents) from Saudi Arabia with an earlier history of three unexplained RPLs at the ninth week of pregnancy was included in the study. Whole-genome sequencing (WGS) of a dead fetus and the parents was done to identify the pathogenic variation and confirmed through Sanger sequencing. WGS of dead fetus identifies a novel homozygous exonic variation (NM_017419.3:c.680G>T) in ASIC5 (acid-sensing ion channel subunit family member 5) gene; the parents are heterozygous. Newly designed ARMS PCR followed by direct sequencing confirms the presence of heterozygous in one subject and absence of homozygous novel mutation among randomly selected healthy Saudis. The second family with heterozygous was confirmed with three unexplained RPLs. Pathogenicity analysis of R227I amino acid substitution in ASIC5 protein through molecular docking and interaction analysis revealed that the mutations are highly pathogenic, decrease the stability of the protein, and prevent binding of amiloride, which is an activator to open the acid-sensing ion channel of ASIC5. The identified rare and novel autosomal recessive mutation, c.680G>T:p.R227I (ASIC5Saudi), in two families confirm the ASIC5 gene association with RPL and can be fatal to the fetus.
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Affiliation(s)
- Nourah H. Al Qahtani
- Department of Obstetrics and Gynaecology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Sayed AbdulAzeez
- Department of Genetic Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Noor B. Almandil
- Department of Clinical Pharmacy Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Norah Fahad Alhur
- Department of Genetic Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hind Saleh Alsuwat
- Department of Genetic Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hatoon Ahmed Al Taifi
- Department of Obstetrics and Gynaecology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Ahlam A. Al-Ghamdi
- Department of Obstetrics and Gynaecology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - B. Rabindran Jermy
- Department of Nanomedicine Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohamed Abouelhoda
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Shazia Subhani
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Lubna Al Asoom
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - J. Francis Borgio
- Department of Genetic Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Department of Epidemic Diseases Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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37
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Altuame FD, Shamseldin HE, Albatti TH, Hashem M, Ewida N, Abdulwahab F, Alkuraya FS. PLXNA2 as a candidate gene in patients with intellectual disability. Am J Med Genet A 2021; 185:3859-3865. [PMID: 34327814 DOI: 10.1002/ajmg.a.62440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 07/03/2021] [Accepted: 07/09/2021] [Indexed: 11/09/2022]
Abstract
Intellectual disability (ID) is one of the most common disabilities in humans. In an effort to contribute to the expanding genetic landscape of ID, we describe a novel autosomal recessive ID candidate gene. Combined autozygome/exome analysis was performed in two unrelated consanguineous families with ID. Each of the two families had a novel homozygous likely deleterious variant in PLXNA2 and displayed the core phenotype of ID. PLXNA2 belongs to a family of transmembrane proteins that function as semaphorin receptors. Sema5A-PlexinA2 is known to regulate brain development in mouse, and Plxna2-/- mice display defective associative learning, sociability, and sensorimotor gating. We note the existence of variability in the phenotype among the three patients, including the existence of variable degree of ID, ranging from borderline intellectual functioning to moderate-severe ID, and the presence of cardiac anomalies in only one of the patients. We propose incomplete penetrance as a possible explanation of the observed difference in phenotypes. Future cases will be needed to support the proposed link between PLXNA2 and ID in humans.
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Affiliation(s)
- Fadie D Altuame
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Hanan E Shamseldin
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Turki H Albatti
- Abdullatif Al Fozan Center for Autism, Alkhobar, Saudi Arabia.,Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mais Hashem
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nour Ewida
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Firdous Abdulwahab
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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38
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Burdon KP. The utility of genomic testing in the ophthalmology clinic: A review. Clin Exp Ophthalmol 2021; 49:615-625. [PMID: 34231298 DOI: 10.1111/ceo.13970] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/25/2022]
Abstract
Genomic testing assesses many genes in one test. It is often used in the diagnosis of heterogeneous single gene disorders where pathogenic variation in one of many genes are known to cause similar phenotypes, or where a clinical diagnosis is difficult to reach. In the ophthalmic setting, genomic testing can be used to diagnose several groups of diseases, including inherited retinal dystrophies, paediatric cataract, glaucoma and anterior segment dysgenesis and other syndromic developmental disorders with eye involvement. The testing can encompass several modalities ranging from whole genome sequencing to exome sequencing or targeted gene panels. The advantages to the patient of receiving a molecular diagnosis include an end to the diagnostic odyssey, determination of prognosis and clarification of treatment, access to accurate genetic counselling, and confirming eligibility for clinical trials or genetic specific therapies. Genomic testing is a powerful addition to the diagnosis and management of inherited eye disease.
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Affiliation(s)
- Kathryn P Burdon
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
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39
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Molecular classification of blood and bleeding disorder genes. NPJ Genom Med 2021; 6:62. [PMID: 34272389 PMCID: PMC8285395 DOI: 10.1038/s41525-021-00228-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
The advances and development of sequencing techniques and data analysis resulted in a pool of informative genetic data, that can be analyzed for informing decision making in designing national screening, prevention programs, and molecular diagnostic tests. The accumulation of molecular data from different populations widen the scope of utilization of this information. Bleeding disorders are a heterogeneous group of clinically overlapping disorders. We analyzed the targeted sequencing data from ~1285 Saudi individuals in 17 blood and bleeding disorders genes, to determine the frequency of mutations and variants. We used a replication set of ~5000 local exomes to validate pathogenicity and determine allele frequencies. We identified a total of 821 variants, of these 98 were listed in HGMD as disease related variants and 140 were novel variants. The majority of variants were present in VWF, followed by F5, F8, and G6PD genes, while FGG, FGB, and HBA1 had the lowest number of variants. Our analysis generated a priority list of genes, mutations and novel variants. This data will have an impact on informing decisions for screening and prevention programs and in management of vulnerable patients admitted to emergency, surgery, or interventions with bleeding side effects.
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40
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A homozygous loss-of-function mutation in GP1BB causing variable clinical phenotypes in a family with Bernard-Soulier syndrome. Blood Coagul Fibrinolysis 2021; 32:352-355. [PMID: 33657022 DOI: 10.1097/mbc.0000000000001027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Bernard-Soulier syndrome is a rare autosomal recessive bleeding disorder and has a low incidence. Bernard-Soulier syndrome is caused by the deficiency of glycoprotein GPIb-V-IX complex, a receptor for von Willebrand factor and is characterized by thrombocytopenia, giant platelets and bleeding tendency. We are reporting three members of a same family with variable phenotypic clinical presentation. The index case is a 20-year-old boy who has a frequent presentation with epistaxis, and low platelet counts (25 × 109/l). He had been hospitalized multiple times and received platelet transfusions. His brother and cousin reported bleeding symptoms with less frequent medical intervention. Genetic analysis by next-generation sequencing identified a homozygous GP1BB variant (c.423C>A:p.Cys141Ter), which segregated amongst the family members. The results led us to an improved insight into the disease for this family with variable phenotypic expression, in addition to the identification of a variant for further structural and functional characterization.
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Khan AO, AlAbdi L, Patel N, Helaby R, Hashem M, Abdulwahab F, AlBadr FB, Alkuraya FS. Genetic testing results of children suspected to have Stickler syndrome type collagenopathy after ocular examination. Mol Genet Genomic Med 2021; 9:e1628. [PMID: 33951325 PMCID: PMC8172201 DOI: 10.1002/mgg3.1628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/04/2022] Open
Abstract
Purpose Stickler syndrome is a collagenopathy that is typically COL2A1‐related (autosomal dominant) and less commonly related to other collagen gene mutations. Diagnosis is straightforward when a child has myopia or retinal detachment in the setting of classic diagnostic criteria such as hearing impairment, midfacial hypoplasia, and arthropathy. However, some children have primarily ocular disease with mild or no extraocular features. Such children can remain undiagnosed unless suspicion is raised by the ophthalmologist. Methods Retrospective consecutive case series (2014–2016) of children (<12 years old) suspected to have Stickler syndrome type collagenopathy by a single ophthalmologist and able to complete genetic testing for this possibility. Suspicion was based on vitreous abnormalities and myopia or lens opacities in the setting of prior retinal detachment, hearing impairment, or facial flatness. Results Average age of the 12 identified children was 8 years old (range 3–11; five boys). Average spherical equivalent for phakic eyes was −13 (range −3.5 to −30). Nine children had lens opacities or aphakia; two with aphakia also had lens subluxation or iridodonesis. Other recurrent clinical features included flat facies (12/12), hearing impairment (5/12), and prior retinal detachment (4/12). Pathogenic variants for collagenopathy were uncovered in 10/12 children: COL11A1 (heterozygous) in six, COL2A1 (heterozygous) in two, and COL9A1 (homozygous) in two. One child was homozygous for pathogenic variation in LRPAP1. One child had no detectable gene mutations. Conclusions Taken together, these clinical features (particularly vitreous abnormality, myopia, and lens opacity) had a high molecular yield for collagen gene mutation. Ophthalmologists who see such children should suspect Stickler syndrome, even in the absence of overt systemic disease. COL11A1‐related rather than COL2A1‐related autosomal dominant disease may be more common when undiagnosed children are identified based on ocular examination. Biallelic mutations in LRPAP1 can result in a phenotype that may resemble Stickler syndrome.
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Affiliation(s)
- Arif O Khan
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia.,Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.,Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western University, Cleveland, OH, USA
| | - Lama AlAbdi
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia.,College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Nisha Patel
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
| | - Rana Helaby
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
| | - Mais Hashem
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
| | | | - Fahad B AlBadr
- Department of Radiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Fowzan S Alkuraya
- Department of Genetics, KFSHRC, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Molina-Ramírez LP, Kyle C, Ellingford JM, Wright R, Taylor A, Bhaskar SS, Campbell C, Jackson H, Fairclough A, Rousseau A, Burghel GJ, Dutton L, Banka S, Briggs TA, Clayton-Smith J, Douzgou S, Jones EA, Kingston HM, Kerr B, Ealing J, Somarathi S, Chandler KE, Stuart HM, Burkitt-Wright EM, Newman WG, Bruce IA, Black GC, Gokhale D. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders. J Med Genet 2021; 59:393-398. [PMID: 33879512 PMCID: PMC8961756 DOI: 10.1136/jmedgenet-2020-107303] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 01/17/2021] [Accepted: 02/14/2021] [Indexed: 01/20/2023]
Abstract
Purpose The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution. Methods Retrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods. Results Abnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%. Conclusions Our results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
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Affiliation(s)
- Leslie Patricia Molina-Ramírez
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Claire Kyle
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Jamie M Ellingford
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Ronnie Wright
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Algy Taylor
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Sanjeev S Bhaskar
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Christopher Campbell
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Harriet Jackson
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Adele Fairclough
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Abigail Rousseau
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - George J Burghel
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Laura Dutton
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Siddharth Banka
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Tracy A Briggs
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Jill Clayton-Smith
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Sofia Douzgou
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Elizabeth A Jones
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
| | - Helen M Kingston
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Bronwyn Kerr
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - John Ealing
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.,Department of Neurology, Salford Royal NHS Foundation Trust, Salford, Salford, UK
| | - Suresh Somarathi
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Kate E Chandler
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Helen M Stuart
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Emma Mm Burkitt-Wright
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - William G Newman
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Iain A Bruce
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,Paediatric ENT Department, Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
| | - Graeme C Black
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK .,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - David Gokhale
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
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Alsalamah AK, Khan AO, Bakar AA, Schatz P, Nowilaty SR. Recognizable Patterns of Submacular Fibrosis in Enhanced S-Cone Syndrome. Ophthalmol Retina 2021; 5:918-927. [PMID: 33819700 DOI: 10.1016/j.oret.2021.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To highlight recognizable patterns of subretinal fibrosis in enhanced S-cone syndrome (ESCS). DESIGN Retrospective case series. PARTICIPANTS Forty-seven patients with subretinal fibrosis identified from 101 patients with clinically diagnosed ESCS, confirmed by full-field electroretinography (35/47), genetic testing (34/47), or both. METHODS Multimodal retinal imaging, electroretinography, and genetic analysis. MAIN OUTCOME MEASURES Patterns of subretinal fibrosis with angiographic, OCT, and genetic correlations. RESULTS Eighty-five eyes of 47 patients (24 male patients; 36 unrelated consanguineous families) had subretinal fibrosis. Mean age at presentation was 14 years. Best-corrected visual acuity ranged from 20/20 to hand movements. All 34 genetically tested patients were homozygous for pathogenic NR2E3 variants. Subretinal fibrosis was always in the macular area, although it extended beyond in some patients. Six recurrent patterns of submacular fibrosis were noted: central unifocal nodular, circumferential unifocal nodular, multifocal nodular, arcuate, helicoid, and thick geographic. Some patients showed a combination of patterns. Previous misdiagnosis as inflammatory disease was common. Fibrosis was fairly symmetrical in a given patient but not always present or identical in other affected individuals with a given homozygous mutation from the same or other families. CONCLUSIONS These recognizable patterns of submacular fibrosis are part of the ESCS phenotypic spectrum and strongly suggest the disease. In addition to facilitating diagnosis, recognition of these patterns can spare patients unnecessary workup for an inflammatory cause.
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Affiliation(s)
- Abrar K Alsalamah
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Arif O Khan
- Pediatric Ophthalmology Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western University, Cleveland, Ohio
| | - Abdullah Abu Bakar
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Ophthalmology Service, King Khaled Hospital, Najran, Saudi Arabia
| | - Patrik Schatz
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology, Clinical Sciences, Skane County University Hospital, Lund University, Lund, Sweden
| | - Sawsan R Nowilaty
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
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Hildebrandt CC, Patel N, Graham JM, Bamshad M, Nickerson DA, White JJ, Marvin CT, Miller DE, Grand KL, Sanchez-Lara PA, Schweitzer D, Al-Zaidan HI, Al Masseri Z, Alkuraya FS, Lin AE. Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome. Am J Med Genet A 2021; 185:2136-2149. [PMID: 33783941 DOI: 10.1002/ajmg.a.62194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 02/27/2021] [Indexed: 12/29/2022]
Abstract
Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.
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Affiliation(s)
- Clara C Hildebrandt
- Genetics Unit, MassGeneral Hospital for Children, Massachusetts, USA.,Boston Children's Hospital Medical Biochemical Fellowship, Boston, Massachusetts, USA
| | - Nisha Patel
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - John M Graham
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Michael Bamshad
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.,Department of Genome Sciences, University of Washington, Seattle, Washington, USA.,Brotman Baty Institute, Seattle, Washington, USA
| | - Deborah A Nickerson
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA.,Brotman Baty Institute, Seattle, Washington, USA
| | | | - Colby T Marvin
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
| | - Danny E Miller
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.,Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | | | - Katheryn L Grand
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Pedro A Sanchez-Lara
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Daniela Schweitzer
- Division of Pediatric Genetics, Department of Pediatrics, University of California Los Angeles, Los Angeles, California, USA
| | - Hamad I Al-Zaidan
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Zainab Al Masseri
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Angela E Lin
- Genetics Unit, MassGeneral Hospital for Children, Massachusetts, USA
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Al-Mayouf SM, Yateem M, Al-Dusery H, Monies D, Wakil S, AlShiakh M, AlEnazi A, Aladaileh B, Alzyoud R, Meyer B. New or vanishing frontiers: LACC1-associated juvenile arthritis. Int J Pediatr Adolesc Med 2021; 8:44-47. [PMID: 33718577 PMCID: PMC7922844 DOI: 10.1016/j.ijpam.2020.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/24/2020] [Accepted: 11/09/2020] [Indexed: 04/25/2023]
Abstract
BACKGROUND The classification and pathogenic basis of juvenile idiopathic arthritis (JIA) are a subject of some controversy. Essentially, JIA is an exclusion diagnosis that represents a phenotypically heterogeneous group of arthritis of unknown origin. Familial aggregation of JIA supports the concept of genetic influence in the pathogenesis of JIA. OBJECTIVE To present the spectrum of laccase domain-containing 1 (LACC1)-associated juvenile arthritis with clinical, biochemical, and molecular genetic data of a cohort of 43 patients, including 11 previously unpublished cases. METHODS We studied 11 patients with different categories of juvenile idiopathic arthritis from 5 consanguineous families, all from Saudi Arabia, except 2 patients who were of Jordanian ethnicity. Whole-exome sequencing was used to identify the disease-causing variant of LACC1. We also reviewed the clinical spectrum and molecular genetic data of previously published cases of LACC1-associated juvenile arthritis. RESULTS This study describes 43 (29 females, 14 males) patients from consanguineous multiplex families. Most of the included patients were of Arab origin with 86% having early onset disease. The most frequent categories were systemic (19 patients) and rheumatoid factor-negative polyarticular (19 patients). Thirty-seven (86%) had progressive erosive arthritis and 10 (23.3%) had persistent limb lymphedema. None of the patients had features of macrophage activation syndrome. Genetic analysis confirmed LACC1 variant in all patients; 22 patients had common founder mutation (LACC1: c.850T > C,p.C284R), while the others showed different LACC1 variants. All patients were treated aggressively with methotrexate and sequential biologic agents. Most of them showed a poor response to treatment. CONCLUSION This report expands the pathogenic variants of LACC1 and the clinical spectrum associated with this genetic subset of juvenile arthritis. The predominance of autosomal-recessive inheritance and strong genetic evidence allowed us to propose LACC1-associated juvenile arthritis as a distinct disorder.
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Affiliation(s)
- Sulaiman M. Al-Mayouf
- Department of Pediatric Rheumatology, Riyadh, Saudi Arabia
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Corresponding author. Pediatric Rheumatology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Alfaisal University, Po Box 3354, Riyadh, 11211, Saudi Arabia.
| | - Mada Yateem
- Department of Pediatric Rheumatology, Riyadh, Saudi Arabia
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Haya Al-Dusery
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Dorota Monies
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Salma Wakil
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Manal AlShiakh
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | | | | | - Brian Meyer
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Mann N, Mzoughi S, Schneider R, Kühl SJ, Schanze D, Klämbt V, Lovric S, Mao Y, Shi S, Tan W, Kühl M, Onuchic-Whitford AC, Treimer E, Kitzler TM, Kause F, Schumann S, Nakayama M, Buerger F, Shril S, van der Ven AT, Majmundar AJ, Holton KM, Kolb A, Braun DA, Rao J, Jobst-Schwan T, Mildenberger E, Lennert T, Kuechler A, Wieczorek D, Gross O, Ermisch-Omran B, Werberger A, Skalej M, Janecke AR, Soliman NA, Mane SM, Lifton RP, Kadlec J, Guccione E, Schmeisser MJ, Zenker M, Hildebrandt F. Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome. J Am Soc Nephrol 2021; 32:580-596. [PMID: 33593823 PMCID: PMC7920168 DOI: 10.1681/asn.2020040490] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 11/18/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease. METHODS Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified. RESULTS Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes. CONCLUSIONS Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.
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Affiliation(s)
- Nina Mann
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Slim Mzoughi
- Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ronen Schneider
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Susanne J Kühl
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Denny Schanze
- Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany
| | - Verena Klämbt
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Svjetlana Lovric
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Youying Mao
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shasha Shi
- Grenoble Alpes University, National Center for Scientific Research (CNRS), French Alternative Energies and Atomic Energy Commission (CEA), Institute of Structural Biology, Grenoble, France
| | - Weizhen Tan
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Michael Kühl
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Ana C Onuchic-Whitford
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ernestine Treimer
- Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Thomas M Kitzler
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Franziska Kause
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Sven Schumann
- Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Makiko Nakayama
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Florian Buerger
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shirlee Shril
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Amelie T van der Ven
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Amar J Majmundar
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Amy Kolb
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Daniela A Braun
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jia Rao
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tilman Jobst-Schwan
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Eva Mildenberger
- Division of Neonatology, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Thomas Lennert
- Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Alma Kuechler
- Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany
| | - Dagmar Wieczorek
- Institute of Human Genetics, Faculty of Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Oliver Gross
- Clinic of Nephrology and Rheumatology, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany
| | - Beate Ermisch-Omran
- Department of Pediatric Nephrology, University Children's Hospital, Münster, Germany
| | - Anja Werberger
- Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
| | - Martin Skalej
- Institute of Neuroradiology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Andreas R Janecke
- Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Neveen A Soliman
- Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
- The Egyption Group for Orphan Renal Diseases (EGORD), Cairo, Egypt
| | - Shrikant M Mane
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
| | - Richard P Lifton
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
- Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York
| | - Jan Kadlec
- Grenoble Alpes University, National Center for Scientific Research (CNRS), French Alternative Energies and Atomic Energy Commission (CEA), Institute of Structural Biology, Grenoble, France
| | - Ernesto Guccione
- Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Michael J Schmeisser
- Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
- Focus Program Translational Neurosciences, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Martin Zenker
- Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany
| | - Friedhelm Hildebrandt
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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Abstract
Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports. Here we review the utility of genetic testing in patients with neurodevelopmental disorders and describe the three major testing modalities and their yields - chromosomal microarray, exome sequencing (with/without copy number variant calling), and FMR1 CGG repeat analysis for fragile X syndrome. Given the diagnostic yield of genetic testing and the potential for clinical and personal utility, there is consensus that genetic testing should be offered to all patients with global developmental delay, intellectual disability, and/or autism spectrum disorder. Despite this recommendation, data suggest that a minority of children with autism spectrum disorder and intellectual disability have undergone genetic testing. To address this gap in care, we describe a structured but flexible approach to facilitate integration of genetic testing into clinical practice across pediatric specialties and discuss future considerations for genetic testing in neurodevelopmental disorders to prepare pediatric providers to care for patients with such diagnoses today and tomorrow.
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Affiliation(s)
- Juliann M. Savatt
- Autism & Developmental Medicine Institute, Geisinger, Danville, PA, United States
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48
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Nowilaty SR, Alsalamah AK, Magliyah MS, Alabdullah AA, Ahmad K, Semidey VA, Mura M, Schatz P. Incidence and Natural History of Retinochoroidal Neovascularization in Enhanced S-Cone Syndrome. Am J Ophthalmol 2021; 222:174-184. [PMID: 32941856 DOI: 10.1016/j.ajo.2020.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/25/2020] [Accepted: 09/08/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVE We examined the incidence and natural history of macular retinochoroidal neovascularization (RCN) in enhanced S-cone syndrome (ESCS). DESIGN Retrospective case series. METHODS This single-center study included 14 of 93 patients with ESCS who had signs of active or inactive RCN in ≥1 eye. We conducted multimodal retinal imaging, full-field electroretinography, and molecular genetic analysis of NR2E3 gene. Our main outcome measures included the cumulative incidence of RCN in ESCS, type of RCN, and mode of evolution of RCN. RESULTS Fourteen (15.1%) of 93 patients with ESCS had RCN in ≥1 eye at 2 to 27 years of age. All 22 RCNs (21 eyes of 14 patients) were macular. Twelve of the RCNs were active with exudates/hemorrhages. Of these, 5 appeared de novo in a subretinal location, with photographic evidence of no pre-existing lesions. The latter were compatible with type 3 neovascularization or retinal angiomatous proliferation and subsequently evolved into unifocal fibrotic nodules. The remaining active lesions all had some degree of pre-existing fibrosis and remained stable. Ten inactive fibrotic nodules, identical to end-stage de novo lesions, were found and were presumed to represent healed RCNs. CONCLUSIONS RCN, a treatable condition, may occur as early as 2 years of age and may be much more common in patients with ESCS than previously estimated. It may be the primary cause of the unifocal submacular fibrosis that is commonly observed in this condition. Additional research is needed to establish the pathogenesis of RCN in patients with ESCS and its optimal management.
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Affiliation(s)
- Sawsan R Nowilaty
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Abrar K Alsalamah
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Moustafa S Magliyah
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Ophthalmology Department, Prince Mohammed Medical City, AlJouf, Saudi Arabia
| | | | - Khabir Ahmad
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Valmore A Semidey
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Marco Mura
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Ophthalmology Department, University of Illinois, Chicago, Illinois, USA
| | - Patrik Schatz
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Ophthalmology, Clinical Sciences, Skane County University Hospital, Lund University, Lund, Sweden.
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49
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Magliyah M, Alshamrani AA, Schatz P, Taskintuna I, Alzahrani Y, Nowilaty SR. Clinical spectrum, genetic associations and management outcomes of Coats-like exudative retinal vasculopathy in autosomal recessive retinitis pigmentosa. Ophthalmic Genet 2021; 42:178-185. [PMID: 33441055 DOI: 10.1080/13816810.2020.1867754] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Background: Coats-like retinal vasculopathy in retinitis pigmentosa (RP) is rare. This study describes its clinical spectrum, management outcomes and genetic associations in patients with autosomal recessive RP (arRP).Materials and methods: Retrospective review of ophthalmic, multimodal imaging, genetic findings and treatment outcomes of arRP patients who developed Coats-like features. Identification of patients included searching a retinal dystrophy registry of 798 patients.Results: Ten eyes of six patients with arRP (4 males, 2 females, mean age 33 years) demonstrated Coats-like features, namely inferotemporal peripheral retinal telangiectasis combined with unilateral inferotemporal vasoproliferative tumor (VPT) in 4 eyes. Exudative retinal detachment (ERD) developed in five eyes of which four had VPT. Ablation of the vasculopathy using retinal laser photocoagulation and/or cryotherapy in eight eyes, allowed ERD and/or lipid exudation to decrease in seven eyes despite incomplete vasculopathy regression. Additional intravitreal triamcinolone acetonide injection in one eye failed to regress the ERD and associated VPT. Observation in one eye caused increased exudation. Six mutations, including three novel mutations, were found in CRB1, CNGB1, RPGR, and TULP1.Conclusions: Coats-like features in arRP range from retinal telangiectasis to VPTs with extensive ERD and occur predominantly in the inferotemporal retinal periphery. In addition to their classic association with CRB1 mutations, other genes are implicated. To the best of our knowledge, this is the first report describing CNGB1 mutations in Coats-like RP. Awareness of the vasculopathy spectrum is important, and timely ablation of the vasculopathy with long-term monitoring is recommended to prevent additional visual loss in RP patients.
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Affiliation(s)
- Moustafa Magliyah
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | | | - Patrik Schatz
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.,Department of Ophthalmology, Clinical Sciences, Skane County University Hospital, University of Lund, Lund, Sweden
| | - Ibrahim Taskintuna
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Yahya Alzahrani
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.,Ophthalmology Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Sawsan R Nowilaty
- Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
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50
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Chiara M, Mandreoli P, Tangaro MA, D'Erchia AM, Sorrentino S, Forleo C, Horner DS, Zambelli F, Pesole G. VINYL: Variant prIoritizatioN by survivaL analysis. Bioinformatics 2020; 36:5590-5599. [PMID: 33367501 DOI: 10.1093/bioinformatics/btaa1067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 10/31/2020] [Accepted: 12/14/2020] [Indexed: 11/12/2022] Open
Abstract
MOTIVATION Clinical applications of genome re-sequencing technologies typically generate large amounts of data that need to be carefully annotated and interpreted to identify genetic variants potentially associated with pathological conditions. In this context, accurate and reproducible methods for the functional annotation and prioritization of genetic variants are of fundamental importance. RESULTS In this paper, we present VINYL, a flexible and fully automated system for the functional annotation and prioritization of genetic variants. Extensive analyses of both real and simulated datasets suggest that VINYL can identify clinically relevant genetic variants in a more accurate manner compared to equivalent state of the art methods, allowing a more rapid and effective prioritization of genetic variants in different experimental settings. As such we believe that VINYL can establish itself as a valuable tool to assist healthcare operators and researchers in clinical genomics investigations. AVAILABILITY VINYL is available at http://beaconlab.it/VINYL and https://github.com/matteo14c/VINYL. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Matteo Chiara
- Department of Biosciences, University of Milan, Milan, Italy.,Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | | | - Marco Antonio Tangaro
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Anna Maria D'Erchia
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.,Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari "Aldo Moro", Bari, Italy
| | - Sandro Sorrentino
- Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Cinzia Forleo
- Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - David S Horner
- Department of Biosciences, University of Milan, Milan, Italy.,Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Federico Zambelli
- Department of Biosciences, University of Milan, Milan, Italy.,Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.,Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari "Aldo Moro", Bari, Italy
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