|
1
|
Drozdov GV, Kashevarova AA, Lebedev IN. Copy number variations in spontaneous abortions: a meta-analysis. J Assist Reprod Genet 2025:10.1007/s10815-025-03420-w. [PMID: 40019700 DOI: 10.1007/s10815-025-03420-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/02/2025] [Indexed: 03/01/2025] Open
Abstract
The goal of this study was to analyze copy number variations (CNVs) in spontaneous abortions with a euploid karyotype, irrespective of the method used for CNV detection. This systematic review was performed in accordance with the PRISMA guidelines. Articles published between 2006 and 2023 were selected through the PubMed database. Studies were included if they involved CNV analysis in spontaneous abortions using any CNV detection method. The pathogenic significance of CNVs was interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Nineteen publications met the inclusion criteria. A total of 1425 CNVs were identified in 550 samples from 3953 euploid spontaneous abortions, representing 14% of the cases. Among the detected CNVs, 9% were classified as pathogenic, and 7.5% were likely pathogenic. The most frequently observed pathogenic CNVs included 22q11.2 deletion/duplication, 16p13.11 deletion, 15q11.2 deletion/duplication, 1p36.33 duplication, and 17p13.3 duplication. The genomic regions with the highest frequency of CNVs, regardless of their pathogenic effect, were 8q24.3, 16p13.3, 21q22.3, Xp22.33, Xp22.31, and Xq28. No clear associations were found between specific CNVs and pregnancy loss. However, deletions in the 22q11.2 region emerged as the most likely candidates contributing to lethality during the early stages of embryonic development.
Collapse
Affiliation(s)
- Gleb V Drozdov
- Tomsk National Research Medical Center, Research Institute of Medical Genetics, Russian Academy of Sciences, Tomsk, Russia.
| | - Anna A Kashevarova
- Tomsk National Research Medical Center, Research Institute of Medical Genetics, Russian Academy of Sciences, Tomsk, Russia
| | - Igor N Lebedev
- Tomsk National Research Medical Center, Research Institute of Medical Genetics, Russian Academy of Sciences, Tomsk, Russia
| |
Collapse
|
|
2
|
Tang D, Chen A, Xu J, Huang Y, Fan J, Wang J, Zhu H, Pi G, Yang L, Xiong F, Luo Z, Li G, Zeng L, Zhu S. Genetic analysis of partial duplication of the long arm of chromosome 16. BMC Med Genomics 2024; 17:294. [PMID: 39716170 DOI: 10.1186/s12920-024-02059-3] [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: 09/10/2024] [Accepted: 11/27/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND Pure partial trisomy 16q12.1q22.1 is a rare chromosome copy number variant (CNV). The primary clinical phenotypes associated with this syndrome include abnormal facial morphology, global developmental delay (GDD), short stature, and reported predisposing factors for atypical behavior, autism, the development of learning disabilities, and neuropsychiatric disorders. The dosage-sensitive genes associated with partial trisomy are not disclosed preventing to establish a genotype-phenotype correlation. METHODS We report a case of a Chinese patient diagnosed with GDD and an abnormal facial shape, who was found to have partial trisomy 16 through karyotyping and high-throughput sequencing analysis. Karyotype and CNV tracing analyses were also conducted on the biological parents of the patient to assess for any chromosomal structural abnormalities. Additionally, we included 29 patients with pure partial trisomy 16q, reported in the DECIPHER database and the literature. We and performed a genotype-phenotype correlation analysis. RESULTS The proband, a 2-year-old female, was found to have a de novo 21.96 Mb duplication located between 16q12.1q22.1, with no other deletions observed on other chromosomes, indicating a pure partial trisomy of 16q. Through genotype and phenotype analysis of 29 individuals, we found that patients with the duplicated region located at the distal region of 16q may exhibit more severe symptoms than those with duplication at the proximal region; however, no relationship was identified between phenotype and the size of the duplicated segment. CONCLUSION We report, for the first time, a patient with partial trisomy 16q validated by multiple genetic tests, including CNV-seq, whole exome sequencing (WES), and karyotyping. It is speculated that partial trisomy of 16q may be associated with continuous gene duplication. However, functional studies are necessary to identify the causative gene or critical region linked to duplication syndrome of chromosome 16q.
Collapse
Affiliation(s)
- Dan Tang
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Ai Chen
- Department of Pediatrics, The Second People's Hospital of Chengdu City, Chengdu, China
| | - Jing Xu
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Yu Huang
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Jun Fan
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Jin Wang
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Hui Zhu
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Guanghuan Pi
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Li Yang
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Fu Xiong
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Zemin Luo
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Gen Li
- Department of Medical Laboratory, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Lan Zeng
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China.
| | - Shuyao Zhu
- Department of Pediatrics, Sichuan Provincial Woman's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China.
| |
Collapse
|
|
3
|
Cai M, Lin N, Guo N, Huang H, Fan X, Fu M, Zhang M, Xu L. Molecular Genetic and Clinical Characteristics of Fetuses With Chromosome 16 Short-Arm Microdeletions/Microduplications. J Clin Lab Anal 2024; 38:e25132. [PMID: 39665492 DOI: 10.1002/jcla.25132] [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: 08/26/2024] [Revised: 10/19/2024] [Accepted: 11/15/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND The short arm of chromosome 16 is highly susceptible to homologous recombination through nonallelic genes. This results in microdeletions/microduplications that can lead to neurodevelopmental disorders. However, incomplete penetrance and phenotypic diversity after birth exacerbate the uncertainty in prenatal genetic counseling. METHODS A total of 24,000 cases with prenatal diagnoses were retrospectively analyzed. Chromosome microarray analysis (CMA) was performed on 17,000 cases, of which 81 (0.48%) had chromosome 16 short-arm microdeletions/microduplications. RESULTS Of the 81 fetuses with chromosome 16 short-arm microdeletions/microduplications, 36 and 28 had 16p11.2 and 16p13.11 microdeletions/microduplications, respectively. Ten, four, and three fetuses had 16p12.2, 16p13.12p13.11, and 16p13.12p1.3 microdeletions, respectively. Among the 36 fetuses with 16p11.2 microdeletions/microduplications, 33 had abnormal intrauterine ultrasound phenotypes, the most common being skeletal system abnormalities. Among the 28 fetuses with 16p13.11 microdeletions/microduplications, 19 had abnormal intrauterine ultrasound phenotypes, including 15 with abnormal ultrasonic soft markers. Among the 10 fetuses with the 16p12.2 microdeletions, six had abnormal ultrasound findings, and four had skeletal system abnormalities. After genetic counseling, 44 patients were selected and tested for family verification, of which 22 were de novo, while 22 were inherited from phenotypically normal parents. Among the 47 live births, 39 had no abnormalities. CONCLUSION All fetuses with the 16p13.11 microdeletions/microduplications, and 16p12.2, 16p13.12p13.11, and 16p13.12p1.3 microdeletions were healthy after birth. Hence, chromosome 16 short-arm microdeletions/microduplications should not be the sole basis for abandoning pregnancy, and clinicians should consider prenatal diagnostic data to maximize diagnostic accuracy.
Collapse
Affiliation(s)
- Meiying Cai
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Na Lin
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Nan Guo
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Hailong Huang
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Xiangqun Fan
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Meimei Fu
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Min Zhang
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| | - Liangpu Xu
- Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Clinical Research Center for Maternal-Fetal Medicine, National Key Obstetric Clinical Specialty Construction Institution of China, Fuzhou, China
| |
Collapse
|
|
4
|
Mi L, Yao R, Guo W, Wang J, Zhang G, Ye X. Concurrent de novo MACF1 mutation and inherited 16p13.11 microduplication in a preterm newborn with hypotonia, joint hyperlaxity and multiple congenital malformations: a case report. BMC Pediatr 2024; 24:528. [PMID: 39152427 PMCID: PMC11328432 DOI: 10.1186/s12887-024-04628-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 02/07/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 microduplication syndrome results from the duplication of 16p13.11 chromosome copies and is associated with various neurodevelopmental and physiological abnormalities. Both MACF1 and 16p13.11 microduplication have significant impacts on neural development, potentially leading to nerve damage or neurological diseases. This study presents a unique case of a patient simultaneously experiencing a de novo MACF1 mutation and a hereditary 16p13.11 microduplication, which has not been reported previously. CASE PRESENTATION In this report, we describe a Chinese preterm newborn girl exhibiting the typical characteristics of 16.13.11 microduplication syndrome. These features include developmental delay, respiratory issues, feeding problems, muscle weakness, excessive joint movement, and multiple congenital abnormalities. Through whole-exome sequencing, we identified a disease-causing mutation in the MACF1 gene (c.15266T > C / p. Met5089Thr). Additionally, after microarray analysis, we confirmed the presence of a 16p13.11 microduplication (chr16:14,916,289 - 16,315,688), which was inherited from the mother. CONCLUSIONS The patient's clinical presentation, marked by muscle weakness and multiple birth defects, may be attributed to both the de novo MACF1 mutation and the 16p13.11 duplication, which could have further amplified her severe symptoms. Genetic testing for individuals with complex clinical manifestations can offer valuable insights for diagnosis and serve as a reference for genetic counseling for both patients and their families.
Collapse
Affiliation(s)
- Lanlan Mi
- Department of Neonatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruen Yao
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwei Guo
- Department of Neonatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jian Wang
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Guoqing Zhang
- Department of Neonatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiuxia Ye
- Department of Neonatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
5
|
João S, Quental R, Pinto J, Almeida C, Santos H, Dória S. Impact of copy number variants in epilepsy plus neurodevelopment disorders. Seizure 2024; 117:6-12. [PMID: 38277927 DOI: 10.1016/j.seizure.2024.01.009] [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: 12/13/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/28/2024] Open
Abstract
INTRODUCTION Epilepsy, a neurological disorder characterized by recurring unprovoked seizures due to excessive neuronal excitability, is primarily attributed to genetic factors, accounting for an estimated 70 % of cases. Array-comparative genomic hybridization (aCGH) is a crucial genetic test for detecting copy number variants (CNVs) associated with epilepsy. This study aimed to analyze a cohort of epilepsy patients with CNVs detected through aCGH to enhance our understanding of the genetic underpinnings of epilepsy. METHODS A retrospective cross-sectional study was conducted using the aCGH database from the Genetics Department of the Faculty of Medicine of the University of Porto, encompassing 146 patients diagnosed with epilepsy, epileptic encephalopathy, or seizures. Clinical data were collected, and aCGH was performed following established guidelines. CNVs were classified based on ACMG standards, and patients were categorized into four groups according to their clinical phenotype. RESULTS Among the 146 included patients, 94 (64 %) had at least one CNV, with 22 (15.1 %) classified as pathogenic or likely pathogenic. Chromosomes 1, 2, 16, and X were frequently implicated, with Xp22.33 being the most reported region (8 CNVs). The phenotype "Epilepsy and global developmental delay/intellectual disability" showed the highest prevalence of clinically relevant CNVs. Various CNVs were identified across different groups, suggesting potential roles in epilepsy. CONCLUSIONS This study highlights the significance of aCGH in unraveling the genetic basis of epilepsy and tailoring treatment strategies. It contributes valuable insights to the expanding knowledge in the field, emphasizing the need for research to elucidate the diverse genetic causes of epilepsy.
Collapse
Affiliation(s)
- Sofia João
- Department of Pathology - Genetics, Faculty of Medicine, University of Porto, Portugal.
| | - Rita Quental
- Medical Genetics Service, Centro Hospitalar Universitário de São João - CHUSJ, Porto, Portugal.
| | - Joel Pinto
- Department of Pathology - Genetics, Faculty of Medicine, University of Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
| | - Carolina Almeida
- Department of Pathology - Genetics, Faculty of Medicine, University of Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
| | - Helena Santos
- Child and Adolescent Neuroscience Unit, Centro Hospitalar Vila Nova de Gaia/Espinho - CHNVG, Vila Nova de Gaia, Portugal.
| | - Sofia Dória
- Department of Pathology - Genetics, Faculty of Medicine, University of Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
| |
Collapse
|
|
6
|
Kang H, Chen Y, Wang L, Gao C, Li X, Hu Y. Pathogenic recurrent copy number variants in 7,078 pregnancies via chromosomal microarray analysis. J Perinat Med 2024; 52:171-180. [PMID: 38081620 DOI: 10.1515/jpm-2022-0580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 09/30/2023] [Indexed: 02/09/2024]
Abstract
OBJECTIVES To investigate the incidence of pathogenic recurrent CNVs in fetuses with different referral indications and review the intrauterine phenotypic features of each CNV. METHODS A total of 7,078 amniotic fluid samples were collected for chromosome microarray analysis (CMA) and cases carrying pathogenic recurrent CNVs were further studied. RESULTS The highest incidence of pathogenic recurrent CNVs was 2.25 % in fetal ultrasound anomalies (FUA) group. Moreover, regardless of other indications, pregnant women with advanced maternal age have a lower incidence compared with whom less than 35 years old (p<0.05). In total 1.17 % (83/7,078) samples carried pathogenic recurrent CNVs: 20 cases with 22q11.2 recurrent region (12 microdeletion and eight microduplication), 11 with 1q21.1 (five microdeletion and six microduplication) and 16p13.11 (four microdeletion and seven microduplication), 10 with 15q11.2 recurrent microdeletion, seven with Xp22.31 recurrent microdeletion and 16p11.2 (three microdeletion and four microduplication), four with 7q11.23 (two microdeletion and two microduplication), three with 17p11.2 (three microdeletion), 17p12 (two microdeletion and one microduplication) and 17q12 (two microdeletion and one microduplication). The rest ones were rare in this study. CONCLUSIONS Pathogenic recurrent CNVs are more likely to be identified in FUA group. Pregnant women with advanced maternal age have a lower incidence of pathogenic recurrent CNVs. The profile of pathogenic recurrent CNVs between prenatal and postnatal is different, especially in 22q11.2, 1q21.1, 15q13.3 recurrent region and 15q11.2 deletion.
Collapse
Affiliation(s)
- Han Kang
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Yifei Chen
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Lingxi Wang
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Chonglan Gao
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Xingyu Li
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Yu Hu
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| |
Collapse
|
|
7
|
Chen L, Wang L, Zeng Y, Yin D, Tang F, Xie D, Zhu H, Liu H, Wang J. Defining the scope of extended NIPS in Western China: evidence from a large cohort of fetuses with normal ultrasound scans. BMC Pregnancy Childbirth 2023; 23:593. [PMID: 37598172 PMCID: PMC10439619 DOI: 10.1186/s12884-023-05921-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: 03/10/2023] [Accepted: 08/14/2023] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Standard noninvasive prenatal screening(NIPS) is an accurate and reliable method to screen for common chromosome aneuploidies, such as trisomy 21, 18 and 13. Extended NIPS has been used in clinic for not only aneuploidies but also copy number variants(CNVs). Here we aim to define the range of chromosomal abnormalities that should be able to identify by NIPS in order to be an efficient extended screening test for chromosomal abnormalities. METHODS A prospective study was conducted, involving pregnant women without fetal sonographic structural abnormalities who underwent amniocentesis. Prenatal samples were analyzed using copy number variation sequencing(CNV-seq) to identify fetal chromosomal abnormalities. RESULTS Of 28,469 pregnancies included 1,022 (3.59%) were identified with clinically significant fetal chromosome abnormalities, including 587 aneuploidies (2.06%) and 435 (1.53%) pathogenic (P) / likely pathogenic (LP) CNVs. P/LP CNVs were found in all chromosomes, but the distribution was not uniform. Among them, P/LP CNVs in chromosomes 16, 22, and X exhibited the highest frequencies. In addition, P/LP CNVs were most common on distal ends of the chromosomes and in low copy repeat regions. Recurrent microdeletion/microduplication syndromes (MMS) accounted for 40.69% of total P/LP CNVs. The size of most P/LP CNVs (77.47%) was < 3 Mb. CONCLUSIONS In addition to aneuploidies, the scope of extended NIPS should include the currently known P/LP CNVs, especially the regions with recurrent MMS loci, distal ends of the chromosomes, and low copy repeat regions. To be effective detection should include CNVs of < 3 Mb. Meanwhile, sufficient preclinical validation is still needed to ensure the clinical effect of extended NIPS.
Collapse
Affiliation(s)
- Lin Chen
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Li Wang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Yang Zeng
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Daishu Yin
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Feng Tang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Dan Xie
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Hongmei Zhu
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Hongqian Liu
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Block 3 No. 20, Ren Min Nan Road, Wuhou district, 610041, Chengdu, China
| | - Jing Wang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Block 3 No. 20, Ren Min Nan Road, Wuhou district, 610041, Chengdu, China.
| |
Collapse
|
|
8
|
Martin Lorenzo S, Muniz Moreno MDM, Atas H, Pellen M, Nalesso V, Raffelsberger W, Prevost G, Lindner L, Birling MC, Menoret S, Tesson L, Negroni L, Concordet JP, Anegon I, Herault Y. Changes in social behavior with MAPK2 and KCTD13/CUL3 pathways alterations in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders. Front Neurosci 2023; 17:1148683. [PMID: 37465586 PMCID: PMC10350633 DOI: 10.3389/fnins.2023.1148683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/02/2023] [Indexed: 07/20/2023] Open
Abstract
Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behavior and in the novel object test in male carriers from both genetic backgrounds. Interestingly major pathways affecting MAPK1 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behavior are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behavior and understanding the brain mechanisms and specific brain regions that are key to controlling social behavior.
Collapse
Affiliation(s)
- Sandra Martin Lorenzo
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Maria Del Mar Muniz Moreno
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Helin Atas
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Marion Pellen
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Valérie Nalesso
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Wolfgang Raffelsberger
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Geraldine Prevost
- Université de Strasbourg, CNRS, INSERM, CELPHEDIA-PHENOMIN, Institut Clinique de la Souris, Illkirch, France
| | - Loic Lindner
- Université de Strasbourg, CNRS, INSERM, CELPHEDIA-PHENOMIN, Institut Clinique de la Souris, Illkirch, France
| | - Marie-Christine Birling
- Université de Strasbourg, CNRS, INSERM, CELPHEDIA-PHENOMIN, Institut Clinique de la Souris, Illkirch, France
| | - Séverine Menoret
- Nantes Université, CHU Nantes, INSERM, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, Nantes, France
- INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Laurent Tesson
- INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Luc Negroni
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | | | - Ignacio Anegon
- INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Yann Herault
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Université de Strasbourg, CNRS, INSERM, CELPHEDIA-PHENOMIN, Institut Clinique de la Souris, Illkirch, France
| |
Collapse
|
|
9
|
Cai M, Que Y, Chen X, Chen Y, Liang B, Huang H, Xu L, Lin N. 16p13.11 microdeletion/microduplication in fetuses: investigation of associated ultrasound phenotypes, genetic anomalies, and pregnancy outcome follow-up. BMC Pregnancy Childbirth 2022; 22:913. [PMID: 36476185 PMCID: PMC9727942 DOI: 10.1186/s12884-022-05267-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES 16p13.11 microdeletion/microduplication are rare genetic diseases with incomplete penetrance, most of which have been reported in adults and children, with ultrasound phenotyping in fetuses rarely described. Here, we have analyzed prenatal ultrasound phenotypic characteristics associated with 16p13.11 microdeletion/microduplication, in order to improve the understanding, diagnosis and monitoring of this disease in the fetus. METHODS A total of 9000 pregnant women who underwent invasive prenatal diagnosis for karyotyping and SNP-array were retrospectively analyzed in tertiary referral institutions from October 2016 to January 2022. RESULTS SNP-array revealed that 20 fetuses had copy number variation (CNV) in the 16p13.11 region, out of which 5 had 16p13.11 microdeletion and the rest showed microduplication, along with different ultrasound phenotypes. Furthermore, 4/20 cases demonstrated structural abnormalities, while the remaining 16 cases were atypical in ultrasound. Taken together, 16p13.1 microdeletion was closely related to thickened nuchal translucency, while 16p13.11 microduplication was more closely associated with echogenic bowel. Only 5/15 fetuses were verified by pedigree, with one case of 16p13.11 microdeletion being de novo, and the other cases of 16p13.11 microduplication were inherited from one parent. In 4/20 cases, the pregnancy was terminated. Except for one case with short stature and another one who underwent lung cystadenoma surgery, no abnormalities were reported in the other cases during follow-up. CONCLUSION Fetuses with 16p13.11 microdeletion/microduplication had no characteristic phenotype of intrauterine ultrasound and was in good health after birth, thus providing a reference for the perinatal management of such cases.
Collapse
Affiliation(s)
- Meiying Cai
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Yanting Que
- grid.256112.30000 0004 1797 9307College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China
| | - Xuemei Chen
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Yuqing Chen
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Bin Liang
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Hailong Huang
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Liangpu Xu
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| | - Na Lin
- grid.256112.30000 0004 1797 9307 Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fuzhou, China
| |
Collapse
|
|
10
|
Tai DJC, Razaz P, Erdin S, Gao D, Wang J, Nuttle X, de Esch CE, Collins RL, Currall BB, O'Keefe K, Burt ND, Yadav R, Wang L, Mohajeri K, Aneichyk T, Ragavendran A, Stortchevoi A, Morini E, Ma W, Lucente D, Hastie A, Kelleher RJ, Perlis RH, Talkowski ME, Gusella JF. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models. Am J Hum Genet 2022; 109:1789-1813. [PMID: 36152629 PMCID: PMC9606388 DOI: 10.1016/j.ajhg.2022.08.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/23/2022] [Indexed: 01/29/2023] Open
Abstract
Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific.
Collapse
Affiliation(s)
- Derek J C Tai
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Parisa Razaz
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Serkan Erdin
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Dadi Gao
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jennifer Wang
- Center for Quantitative Health, Division of Clinical Research, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Xander Nuttle
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Celine E de Esch
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Ryan L Collins
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Benjamin B Currall
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kathryn O'Keefe
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Nicholas D Burt
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Rachita Yadav
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Lily Wang
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kiana Mohajeri
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Tatsiana Aneichyk
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Ashok Ragavendran
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Alexei Stortchevoi
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Elisabetta Morini
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Weiyuan Ma
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Diane Lucente
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | | | - Raymond J Kelleher
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Roy H Perlis
- Center for Quantitative Health, Division of Clinical Research, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Michael E Talkowski
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
| | - James F Gusella
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
| |
Collapse
|
|
11
|
Xu M, Jiang J, He Y, Gu WY, Jin B. Early-onset ophthalmoplegia, cervical dyskinesia, and lower extremity weakness due to partial deletion of chromosome 16: A case report. World J Clin Cases 2022; 10:9332-9339. [PMID: 36159412 PMCID: PMC9477676 DOI: 10.12998/wjcc.v10.i26.9332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We explored the genotype-phenotype correlation of the novel deletion 16p13.2p12.3 in an 8-year-old child with progressive total ophthalmoplegia, cervical dyskinesia, and lower limb weakness by comparing the patient’s clinical features with previously reported data on adjacent copy number variation (CNV) regions.
CASE SUMMARY Specifically, we first performed whole-exome sequencing, CNV-sequencing, and mitochondrial genome sequencing on the patient and his parents, then applied “MitoExome” (the entire mitochondrial genome and exons of nuclear genes encoding the mitochondrial proteome) analysis to screen for genetic mitochondrial diseases. We identified a de novo 7.23 Mb deletion, covering 16p13.2p12.3, by both whole-exome sequencing and CNV sequencing. We also detected 16p13.11 in the deleted region, which is the recurrent distinct region associated with neurodevelopmental disorder. However, the patient only displayed features of progressive total ophthalmoplegia, cervical dyskinesia, and weakness in his lower limbs without neurodevelopmental disorder. The “MitoExome” sequencing was negative. Brain magnetic resonance imaging revealed non-specific sporadic changes in the occipital parietal lobe and basal ganglia.
CONCLUSION Taken together, these results indicated that 16p13.2p12.3 deletion causes a syndrome with the phenotype of early-onset total ophthalmoplegia. The “MitoExome” analysis is powerful for the differential diagnosis of mitochondrial diseases. We report a novel copy number variant in this case, but further confirmation is required.
Collapse
Affiliation(s)
- Min Xu
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Jiao Jiang
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Yan He
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Wei-Yue Gu
- Chigene (Beijing), Translational Medical Research Center Co. Ltd, Beijing 101111, China
| | - Bo Jin
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| |
Collapse
|
|
12
|
Rodríguez-López R, Gimeno-Ferrer F, do Santos DA, Ferrer-Bolufer I, Luján CG, Alcalá OZ, García-Banacloy A, Cogollos VB, Juan CS. Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes. Curr Genomics 2022; 23:147-162. [PMID: 36777005 PMCID: PMC9878830 DOI: 10.2174/1389202923666220426093436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/30/2021] [Accepted: 02/01/2022] [Indexed: 11/22/2022] Open
Abstract
Background: Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Objective: Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. Methods: The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient's family is also of importance. Results: The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. Conclusion: With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.
Collapse
Affiliation(s)
- Raquel Rodríguez-López
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain;,Address correspondence to this author at the Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Avenida de las Tres Cruces no. 2 46014, Valencia, Spain; Tel: 0034 963 131 800 – 437317; Fax: 0034 963 131 979; E-mail:
| | - Fátima Gimeno-Ferrer
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | - David Albuquerque do Santos
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | - Irene Ferrer-Bolufer
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | - Carola Guzmán Luján
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | - Otilia Zomeño Alcalá
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | - Amor García-Banacloy
- Laboratory of Molecular Genetics, Clinical Analysis Service, General Hospital Consortium of Valencia, Valencia, Spain
| | | | - Carlos Sánchez Juan
- Endocrinology Service, General Hospital Consortium of Valencia, Valencia, Spain
| |
Collapse
|
|
13
|
Arslan AB, Zamani AG, Yıldırım MS. Novel Findings, Mini-Review and Dysmorphological Characterization of 16p13.11 Microduplication syndrome. Int J Dev Neurosci 2022; 82:289-294. [PMID: 35470466 DOI: 10.1002/jdn.10188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/25/2022] [Accepted: 04/12/2022] [Indexed: 11/07/2022] Open
Abstract
The short arm of chromosome 16 and especially the region 16p13.11 is a chromosome region where many structural variants, especially deletions and duplications, can be observed. While deletions of this region are clinically well defined, duplications are rare, and so far, there is no established clinical consensus in regard with its clinical picture, and especially the dysmorphic perspective of the disease is far from being clear. A 5-year-and-2-month-old patient who presented with epilepsy, autism and late speech onset complaints, was evaluated in our genetics department. On physical examination unilateral preauricular skin tag and upslanting palpebral fissures were noted. Microarray analysis was performed and reported as ([hg19]: 16p13.11 (14.897.804-16.730.375) x3). The literature review revealed only a few reports about the syndrome, but some dysmorphological findings appear to recur in different reports, which enables a possible characterization. Dysmorphic findings were discussed.
Collapse
Affiliation(s)
- Ahmet Burak Arslan
- Medical Genetics Department, Necmettin Erbakan University Hospital, Konya, Turkey
| | - Ayşe Gül Zamani
- Medical Genetics Department, Necmettin Erbakan University Hospital, Konya, Turkey
| | | |
Collapse
|
|
14
|
Redaelli S, Conconi D, Sala E, Villa N, Crosti F, Roversi G, Catusi I, Valtorta C, Recalcati MP, Dalprà L, Lavitrano M, Bentivegna A. Characterization of Chromosomal Breakpoints in 12 Cases with 8p Rearrangements Defines a Continuum of Fragility of the Region. Int J Mol Sci 2022; 23:ijms23063347. [PMID: 35328767 PMCID: PMC8954119 DOI: 10.3390/ijms23063347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/29/2022] Open
Abstract
Improvements in microarray-based comparative genomic hybridization technology have allowed for high-resolution detection of genome wide copy number alterations, leading to a better definition of rearrangements and supporting the study of pathogenesis mechanisms. In this study, we focused our attention on chromosome 8p. We report 12 cases of 8p rearrangements, analyzed by molecular karyotype, evidencing a continuum of fragility that involves the entire short arm. The breakpoints seem more concentrated in three intervals: one at the telomeric end, the others at 8p23.1, close to the beta-defensin gene cluster and olfactory receptor low-copy repeats. Hypothetical mechanisms for all cases are described. Our data extend the cohort of published patients with 8p aberrations and highlight the need to pay special attention to these sequences due to the risk of formation of new chromosomal aberrations with pathological effects.
Collapse
Affiliation(s)
- Serena Redaelli
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
| | - Donatella Conconi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
- Correspondence: (D.C.); (A.B.)
| | - Elena Sala
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (E.S.); (N.V.); (F.C.)
| | - Nicoletta Villa
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (E.S.); (N.V.); (F.C.)
| | - Francesca Crosti
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (E.S.); (N.V.); (F.C.)
| | - Gaia Roversi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (E.S.); (N.V.); (F.C.)
| | - Ilaria Catusi
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (I.C.); (C.V.); (M.P.R.)
| | - Chiara Valtorta
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (I.C.); (C.V.); (M.P.R.)
| | - Maria Paola Recalcati
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (I.C.); (C.V.); (M.P.R.)
| | - Leda Dalprà
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (E.S.); (N.V.); (F.C.)
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
| | - Angela Bentivegna
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (G.R.); (L.D.); (M.L.)
- Correspondence: (D.C.); (A.B.)
| |
Collapse
|
|
15
|
Inzaghi E, Deodati A, Loddo S, Mucciolo M, Verdecchia F, Sallicandro E, Catino G, Cappa M, Novelli A, Cianfarani S. Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype. J Endocrinol Invest 2022; 45:79-87. [PMID: 34255311 DOI: 10.1007/s40618-021-01617-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/14/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. SUBJECTS AND METHODS Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. RESULTS CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. CONCLUSIONS These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.
Collapse
Affiliation(s)
- E Inzaghi
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy.
| | - A Deodati
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - S Loddo
- Translational Cytogenomics Research Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - M Mucciolo
- Translational Cytogenomics Research Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - F Verdecchia
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - E Sallicandro
- Translational Cytogenomics Research Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - G Catino
- Translational Cytogenomics Research Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - M Cappa
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - A Novelli
- Translational Cytogenomics Research Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - S Cianfarani
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden
| |
Collapse
|
|
16
|
Cheng MC, Chien WH, Huang YS, Fang TH, Chen CH. Translational Study of Copy Number Variations in Schizophrenia. Int J Mol Sci 2021; 23:ijms23010457. [PMID: 35008879 PMCID: PMC8745588 DOI: 10.3390/ijms23010457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/11/2021] [Accepted: 12/29/2021] [Indexed: 11/16/2022] Open
Abstract
Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.
Collapse
Affiliation(s)
- Min-Chih Cheng
- Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 981, Taiwan;
| | - Wei-Hsien Chien
- Department of Occupational Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Yu-Shu Huang
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan;
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Ting-Hsuan Fang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Chia-Hsiang Chen
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan;
- Department and Institute of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence:
| |
Collapse
|
|
17
|
Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing. CEREBELLUM (LONDON, ENGLAND) 2021; 21:1144-1150. [PMID: 34846692 DOI: 10.1007/s12311-021-01350-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/22/2021] [Indexed: 10/19/2022]
Abstract
Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.
Collapse
|
|
18
|
Wu H, Huang Q, Zhang X, Yu Z, Zhong Z. Analysis of Genomic Copy Number Variation in Miscarriages During Early and Middle Pregnancy. Front Genet 2021; 12:732419. [PMID: 34603391 PMCID: PMC8484914 DOI: 10.3389/fgene.2021.732419] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
The purpose of this study was to explore the copy number variations (CNVs) associated with miscarriage during early and middle pregnancy and provide useful genetic guidance for pregnancy and prenatal diagnosis. A total of 505 fetal specimens were collected and CNV sequencing (CNV-seq) analysis was performed to determine the types and clinical significance of CNVs, and relevant medical records were collected. The chromosomal abnormality rate was 54.3% (274/505), among which the numerical chromosomal abnormality rate was 40.0% (202/505) and structural chromosomal abnormality rate was 14.3% (72/505). Chromosomal monosomy mainly occurred on sex chromosomes, and chromosomal trisomy mainly occurred on chromosomes 16, 22, 21, 15, 13, and 9. The incidence of numerical chromosomal abnormalities in ≥35 year-old age pregnant women was significantly higher than <35 year-old age group. The highest incidence of pathogenic CNV (pCNV) was found in fetuses at ≤6 weeks of pregnancy (5.26%), and the incidence of variants of unknown significance (VOUS) CNVs decreased gradually with the increase of gestational age. The rate of chromosomal abnormalities of fetuses in early pregnancy (59.5%) was higher than that of fetuses in middle pregnancy (27.2%) (p < 0.001). There were 168 genes in VOUS + pCNV regions. 41 functions and 12 pathways (p < 0.05) were enriched of these genes by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Some meaningful genetic etiology information such as genes and pathways has been obtained, it may provide useful genetic guidance for pregnancy and prenatal diagnosis.
Collapse
Affiliation(s)
- Heming Wu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Qingyan Huang
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Xia Zhang
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Center for Prenatal Diagnosis, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Zhikang Yu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Zhixiong Zhong
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| |
Collapse
|
|
19
|
Reynard P, Monin P, Veuillet E, Thai-Van H. A new genetic variant causing auditory neuropathy: A CARE case report. Eur Ann Otorhinolaryngol Head Neck Dis 2021; 139:91-94. [PMID: 34456167 DOI: 10.1016/j.anorl.2021.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Auditory neuropathy refers to impaired synchronization of the auditory signal along the cochlear nerve. The present study, following CARE case report guidelines, describes a case of auditory neuropathy secondary to a genetic variant not previously described. OBSERVATION An 18-year-old patient was followed for multiple learning disorder. His main complaint was speech comprehension, especially in noise. Auditory neuropathy was diagnosed on electrophysiological criteria, linked to a 2.66Mb deletion on the short arm of chromosome 16, at 16p13.11p12.3 (15,492,317-18,162,167, according to the hg19 version of the human reference genome). Adapted speech therapy sessions with auditory training for intelligibility in noise and a hearing aid with high-frequency microphone were prescribed. At 6months, the patient reported improvement in understanding speech in noise. CONCLUSION The involvement of this 16p13.11 deletion in the patient's symptomatology was not obvious, in a probable context of incomplete penetrance and variable expression. Early diagnosis of auditory neuropathy allowed implementation of better adapted multidisciplinary specialized management.
Collapse
Affiliation(s)
- P Reynard
- Université Claude Bernard Lyon 1, 69000 Lyon, France; Service d'audiologie et d'explorations otoneurologiques, hospices civils de Lyon, 69002 Lyon, France; Institut de l'audition, Centre de l'Institut Pasteur, Inserm 1120 (Génétique et Physiologie de l'Audition), 75012 Paris, France; Université Paris la Sorbonne, 75006 Paris, France.
| | - P Monin
- Service de génétique médicale, unité de génétique clinique, hospices civils de Lyon, 69002 Lyon, France
| | - E Veuillet
- Université Claude Bernard Lyon 1, 69000 Lyon, France; Service d'audiologie et d'explorations otoneurologiques, hospices civils de Lyon, 69002 Lyon, France; Institut de l'audition, Centre de l'Institut Pasteur, Inserm 1120 (Génétique et Physiologie de l'Audition), 75012 Paris, France
| | - H Thai-Van
- Université Claude Bernard Lyon 1, 69000 Lyon, France; Service d'audiologie et d'explorations otoneurologiques, hospices civils de Lyon, 69002 Lyon, France; Institut de l'audition, Centre de l'Institut Pasteur, Inserm 1120 (Génétique et Physiologie de l'Audition), 75012 Paris, France
| |
Collapse
|
|
20
|
Zhang X, Huang Q, Yu Z, Wu H. Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next-generation sequencing analysis. J Gene Med 2021; 23:e3383. [PMID: 34342101 PMCID: PMC9285438 DOI: 10.1002/jgm.3383] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/21/2021] [Accepted: 07/30/2021] [Indexed: 12/17/2022] Open
Abstract
Background The present study aimed to explore the etiological relationship between miscarriage and stillbirth and copy number variations (CNVs), as well as provide useful genetic guidance for high‐risk pregnancy. Methods In total, 659 fetal samples were recruited and subjected to DNA extraction and CNV sequencing (CNV‐seq), relevant medical records were collected. Results There were 322 cases (48.86%) with chromosomal abnormalities, including 230 with numerical abnormalities and 92 with structural abnormalities. Chromosomal monosomy variations mainly occurred on sex chromosomes and trisomy variations mainly occurred on chromosomes 16, 22, 21, 18, 13 and 15. In total, 41 pathogenic CNVs (23 microdeletions and 18 microduplications) were detected in 27 fetal tissues. The rates of numerical chromosomal abnormalities were 29.30% (109/372), 32.39% (57/176) and 57.66% (64/111) in < 30‐year‐old, 30–34‐year‐old and ≥ 35‐year‐old age pregnant women, respectively, and increased with an increasing age (p < 0.001). There was statistically significant difference (χ2 = 7.595, p = 0.022) in the rates of structural chromosomal abnormalities in these groups (13.71%, 18.75% and 7.21%, respectively). The rates of numerical chromosomal abnormalities were 45.44% (219/482), 7.80% (11/141) and 0% (0/36) in the ≤ 13 gestational weeks, 14–27 weeks and ≥ 28 weeks groups, respectively, and decreased with respect to the increasing gestational age of the fetuses (p < 0.001). Conclusions The present study has obtained useful and accurate genetic etiology information that will provide useful genetic guidance for high‐risk pregnancies.
Collapse
Affiliation(s)
- Xia Zhang
- Center for Prenatal Disgnosis, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Qingyan Huang
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Zhikang Yu
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Heming Wu
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China.,Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| |
Collapse
|
|
21
|
Mosley TJ, Johnston HR, Cutler DJ, Zwick ME, Mulle JG. Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders. BMC Med Genomics 2021; 14:154. [PMID: 34107974 PMCID: PMC8190997 DOI: 10.1186/s12920-021-00999-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 06/02/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. METHODS We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. RESULTS We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10-14). CONCLUSIONS Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.
Collapse
Affiliation(s)
- Trenell J Mosley
- Graduate Program in Genetics and Molecular Biology, Laney Graduate School, Emory University, 201 Dowman Drive, Atlanta, GA, 30322, USA
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Building Suite 300, Atlanta, GA, 30322, USA
| | - H Richard Johnston
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Building Suite 300, Atlanta, GA, 30322, USA
- Emory Integrated Computational Core, Emory University, 101 Woodruff Circle, Atlanta, GA, 30322, USA
| | - David J Cutler
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Building Suite 300, Atlanta, GA, 30322, USA
| | - Michael E Zwick
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Building Suite 300, Atlanta, GA, 30322, USA
- Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA, 30322, USA
| | - Jennifer G Mulle
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Building Suite 300, Atlanta, GA, 30322, USA.
- Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Atlanta, GA, 30322, USA.
| |
Collapse
|
|
22
|
Mulle JG, Sullivan PF, Hjerling-Leffler J. Editorial overview: Rare CNV disorders and neuropsychiatric phenotypes: opportunities, challenges, solutions. Curr Opin Genet Dev 2021; 68:iii-ix. [PMID: 34059379 PMCID: PMC8722467 DOI: 10.1016/j.gde.2021.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Jennifer Gladys Mulle
- Department of Human Genetics, Emory University School of Medicine, Atlanta GA 30322, United States.
| | - Patrick F Sullivan
- Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, United States; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
| | - Jens Hjerling-Leffler
- Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
| |
Collapse
|
|
23
|
Human Chromosome 18 and Acrocentrics: A Dangerous Liaison. Int J Mol Sci 2021; 22:ijms22115637. [PMID: 34073228 PMCID: PMC8198063 DOI: 10.3390/ijms22115637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 12/01/2022] Open
Abstract
The presence of thousands of repetitive sequences makes the centromere a fragile region subject to breakage. In this study we collected 31 cases of rearrangements of chromosome 18, of which 16 involved an acrocentric chromosome, during genetic screening done in three centers. We noticed a significant enrichment of reciprocal translocations between the centromere of chromosome 18 and the centromeric or pericentromeric regions of the acrocentrics. We describe five cases with translocation between chromosome 18 and an acrocentric chromosome, and one case involving the common telomere regions of chromosomes 18p and 22p. In addition, we bring evidence to support the hypothesis that chromosome 18 preferentially recombines with acrocentrics: (i) the presence on 18p11.21 of segmental duplications highly homologous to acrocentrics, that can justify a NAHR mechanism; (ii) the observation by 2D-FISH of the behavior of the centromeric regions of 18 respect to the centromeric regions of acrocentrics in the nuclei of normal subjects; (iii) the contact analysis among these regions on published Hi-C data from the human lymphoblastoid cell line (GM12878).
Collapse
|
|
24
|
Granocchio E, Gazzola S, Scopelliti MR, Criscuoli L, Airaghi G, Sarti D, Magazù S. Evaluation of oro-phonatory development and articulatory diadochokinesis in a sample of Italian children using the protocol of Robbins & Klee. JOURNAL OF COMMUNICATION DISORDERS 2021; 91:106101. [PMID: 33894654 DOI: 10.1016/j.jcomdis.2021.106101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/01/2021] [Accepted: 03/15/2021] [Indexed: 06/12/2023]
Abstract
PURPOSE The Italian version (Granocchio et al., 2019) of the protocol proposed by Robbins and Klee (1987) allows the assessment of structure of the vocal tract, oromotor and oro-phonatory ability, and articulatory diadochokinesis in children. The aim of this study was to collect the first normative sample of Italian children. METHODS We measured the total structural score (TSS), total functional score (TFS), oral function score (OFS), phonatory function score (PFS), maximum phonation time (MPT), speed of monosyllable repetition (SMR), and speed of polysyllable repetition (SPR) in 191 typically developing Italian children aged 2.6-6.11 years. RESULTS Like the finding observed in the original protocol, there were no significant age-related changes in TSS, but the correlation was observed for TFS, OFS, PFS, MPT, SMR and SPR. The Inter-observer agreement was "good" or "excellent" for all scores except for SPR that was "moderate". CONCLUSIONS The increase in oro-motor, oro-phonatory and diadochokinetic abilities confirmed the progressive maturation of these functions with age. The protocol can therefore be considered a useful instrument to classify speech sound disorders (SSDs) by excluding alterations in anatomical structures and evaluate the motor impairment. This normative sample of Italian children allows to use these measures for diagnostic purposes in young Italian speakers.
Collapse
Affiliation(s)
- Elisa Granocchio
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| | - Stefania Gazzola
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| | - Maria Rosa Scopelliti
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| | | | - Gloria Airaghi
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| | - Daniela Sarti
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| | - Santina Magazù
- Language and Learning Disorders Service, Development Neurology Unit, Fondazione I.R.R.C.S. Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
| |
Collapse
|
|
25
|
Tapial S, García JL, Corchete L, Holowatyj AN, Pérez J, Rueda D, Urioste M, González-Sarmiento R, Perea J. Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer. Eur J Hum Genet 2021; 29:709-713. [PMID: 33268847 PMCID: PMC8115567 DOI: 10.1038/s41431-020-00774-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 10/06/2020] [Accepted: 11/12/2020] [Indexed: 01/21/2023] Open
Abstract
Copy neutral loss of heterozygosity (cnLOH) is a common event in several human malignancies-positing this as a mechanism of carcinogenesis. However, the role of cnLOH in synchronous colorectal cancer (SCRC), a unique CRC subtype, is not well understood. The aim of this study was to establish a cnLOH profile of SCRC using a single-nucleotide polymorphism array (SNP-A), and to explore associations between cnLOH and the genomic landscape of frequently mutated genes in SCRC. Among 74 paired SCRC cases, the most frequently altered regions were 16p11.2-p11.1 (59.5%) and 11p11.2-p11.12 (28.4%). Notably, the 6q11.21-q11.22 region altered by cnLOH was uniquely associated with polyclonal SCRCs (p = 0.038). Together, our analysis suggests that inactivation of tumor suppressor genes and cnLOH are rare events among SCRC cases. This study defines distinct patterns of cnLOH in SCRC, and provides initial evidence of a role for cnLOH in SCRC etiology.
Collapse
Affiliation(s)
- Sandra Tapial
- Digestive Cancer Research Unit, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - Juan Luis García
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Luis Corchete
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Andreana N Holowatyj
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Jessica Pérez
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Daniel Rueda
- Digestive Cancer Research Unit, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain
| | - Rogelio González-Sarmiento
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - José Perea
- Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
- Health Research Institute Fundación Jiménez Díaz, Madrid, Spain.
| |
Collapse
|
|
26
|
Characterization of Copy-Number Variations and Possible Candidate Genes in Recurrent Pregnancy Losses. Genes (Basel) 2021; 12:genes12020141. [PMID: 33499090 PMCID: PMC7911754 DOI: 10.3390/genes12020141] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/09/2021] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
It is well established that embryonic chromosomal abnormalities (both in the number of chromosomes and the structure) account for 50% of early pregnancy losses. However, little is known regarding the potential differences in the incidence and distribution of chromosomal abnormalities between patients with sporadic abortion (SA) and recurrent pregnancy loss (RPL), let alone the role of submicroscopic copy-number variations (CNVs) in these cases. The aim of the present study was to systematically evaluate the role of embryonic chromosomal abnormalities and CNVs in the etiology of RPL compared with SA. Over a 3-year period, 1556 fresh products of conception (POCs) from miscarriage specimens were investigated using single nucleotide polymorphism array (SNP-array) and CNV sequencing (CNV-seq) in this study, along with further functional enrichment analysis. Chromosomal abnormalities were identified in 57.52% (895/1556) of all cases. Comparisons of the incidence and distributions of chromosomal abnormalities within the SA group and RPL group and within the different age groups were performed. Moreover, 346 CNVs in 173 cases were identified, including 272 duplications, 2 deletions and 72 duplications along with deletions. Duplications in 16q24.3 and 16p13.3 were significantly more frequent in RPL cases, and thereby considered to be associated with RPL. There were 213 genes and 131 signaling pathways identified as potential RPL candidate genes and signaling pathways, respectively, which were centered primarily on six functional categories. The results of the present study may improve our understanding of the etiologies of RPL and assist in the establishment of a population-based diagnostic panel of genetic markers for screening RPL amongst Chinese women.
Collapse
|
|
27
|
Oliva-Teles N, de Stefano MC, Gallagher L, Rakic S, Jorge P, Cuturilo G, Markovska-Simoska S, Borg I, Wolstencroft J, Tümer Z, Harwood AJ, Kodra Y, Skuse D. Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E9253. [PMID: 33321999 PMCID: PMC7763014 DOI: 10.3390/ijerph17249253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/24/2020] [Accepted: 12/05/2020] [Indexed: 11/17/2022]
Abstract
Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4-BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers' cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.
Collapse
Affiliation(s)
- Natália Oliva-Teles
- Centro de Genética Médica Doutor Jacinto Magalhães/Centro Hospitalar Universitário do Porto, 4099-001 Porto, Portugal;
- Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto (UMIB/ICBAS/UP), 4050-313 Porto, Portugal
| | - Maria Chiara de Stefano
- Italian National Transplant Center, Italian National Institute of Health, 00161 Rome, Italy;
| | - Louise Gallagher
- Trinity Institute of Neurosciences, Trinity College Dublin, University of Dublin, 152-160 Dublin, Ireland;
| | - Severin Rakic
- Public Health Institute of Republic of Srpska, 78000 Banja Luka, Bosnia and Herzegovina;
| | - Paula Jorge
- Centro de Genética Médica Doutor Jacinto Magalhães/Centro Hospitalar Universitário do Porto, 4099-001 Porto, Portugal;
- Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto (UMIB/ICBAS/UP), 4050-313 Porto, Portugal
| | - Goran Cuturilo
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Department of Medical Genetics, University Children’s Hospital, Tirsova 10, 11000 Belgrade, Serbia
| | | | - Isabella Borg
- Department of Pathology, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
- Medical Genetics Unit, Mater Dei Hospital, MSD 2090 L-Imsida, Malta
| | - Jeanne Wolstencroft
- UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; (J.W.); (D.S.)
| | - Zeynep Tümer
- Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhangen, Denmark;
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Adrian J. Harwood
- Neuroscience and Mental Health Research Institute (NMHRI), & School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK;
| | - Yllka Kodra
- National Centre for Rare Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - David Skuse
- UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; (J.W.); (D.S.)
| |
Collapse
|
|
28
|
Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes. Sci Rep 2020; 10:15094. [PMID: 32934329 PMCID: PMC7493916 DOI: 10.1038/s41598-020-72157-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/06/2020] [Indexed: 11/22/2022] Open
Abstract
Many fetuses are found to have ultrasonic abnormalities in the late pregnancy. The association of fetal ultrasound abnormalities in late pregnancy with copy number variations (CNVs) is unclear. We attempted to explore the relationship between types of ultrasonically abnormal late pregnancy fetuses and CNVs. Fetuses (n = 713) with ultrasound-detected abnormalities in late pregnancy and normal karyotypes were analyzed. Of these, 237 showed fetal sonographic structural malformations and 476 showed fetal non-structural abnormalities. Single nucleotide polymorphism (SNP)-based chromosomal microarray (CMA) was performed on the Affymetrix CytoScan HD platform. Using the SNP array, abnormal CNVs were detected in 8.0% (57/713) of the cases, with pathogenic CNVs in 32 cases and variants of uncertain clinical significance (VUS) in 25 cases. The detection rate of abnormal CNVs in fetuses with sonographic structural malformations (12.7%, 30/237) was significantly higher (P = 0.001) than that in the fetuses with non-structural abnormalities (5.7%, 27/476). Overall, we observed that when fetal sonographic structural malformations or non-structural abnormalities occurred in the third trimester of pregnancy, the use of SNP analysis could improve the accuracy of prenatal diagnosis and reduce the rate of pregnancy termination.
Collapse
|
|
29
|
Delihas N. Genesis of Non-Coding RNA Genes in Human Chromosome 22-A Sequence Connection with Protein Genes Separated by Evolutionary Time. Noncoding RNA 2020; 6:E36. [PMID: 32899105 PMCID: PMC7549372 DOI: 10.3390/ncrna6030036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/17/2020] [Accepted: 09/01/2020] [Indexed: 12/11/2022] Open
Abstract
A small phylogenetically conserved sequence of 11,231 bp, termed FAM247, is repeated in human chromosome 22 by segmental duplications. This sequence forms part of diverse genes that span evolutionary time, the protein genes being the earliest as they are present in zebrafish and/or mice genomes, and the long noncoding RNA genes and pseudogenes the most recent as they appear to be present only in the human genome. We propose that the conserved sequence provides a nucleation site for new gene development at evolutionarily conserved chromosomal loci where the FAM247 sequences reside. The FAM247 sequence also carries information in its open reading frames that provides protein exon amino acid sequences; one exon plays an integral role in immune system regulation, specifically, the function of ubiquitin-specific protease (USP18) in the regulation of interferon. An analysis of this multifaceted sequence and the genesis of genes that contain it is presented.
Collapse
Affiliation(s)
- Nicholas Delihas
- Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, NY 11794-5222, USA
| |
Collapse
|
|
30
|
Lengyel A, Pinti É, Pikó H, Jávorszky E, David D, Tihanyi M, Gönczi É, Kiss E, Tóth Z, Tory K, Fekete G, Haltrich I. Clinical and genetic findings in Hungarian pediatric patients carrying chromosome 16p copy number variants and a review of the literature. Eur J Med Genet 2020; 63:104027. [PMID: 32758661 DOI: 10.1016/j.ejmg.2020.104027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/10/2020] [Accepted: 07/25/2020] [Indexed: 11/27/2022]
Abstract
The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature.
Collapse
Affiliation(s)
- Anna Lengyel
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary.
| | - Éva Pinti
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Henriett Pikó
- I Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Eszter Jávorszky
- I Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Dezső David
- Department of Human Genetics, National Health Institute Dr. Ricardo Jorge, Lisbon, Portugal
| | - Mariann Tihanyi
- Department of Genetics, Zala County Hospital, Zalaegerszeg, Hungary
| | - Éva Gönczi
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Eszter Kiss
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Tóth
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Kálmán Tory
- I Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - György Fekete
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Irén Haltrich
- II Department of Pediatrics, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
31
|
Redaelli S, Conconi D, Villa N, Sala E, Crosti F, Corti C, Catusi I, Garzo M, Romitti L, Martinoli E, Patrizi A, Malgara R, Recalcati MP, Dalprà L, Lavitrano M, Riva P, Roversi G, Bentivegna A. Instability of Short Arm of Acrocentric Chromosomes: Lesson from Non-Acrocentric Satellited Chromosomes. Report of 24 Unrelated Cases. Int J Mol Sci 2020; 21:ijms21103431. [PMID: 32413994 PMCID: PMC7279238 DOI: 10.3390/ijms21103431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 01/13/2023] Open
Abstract
Satellited non-acrocentric autosomal chromosomes (ps–qs-chromosomes) are the result of an interchange between sub- or telomeric regions of autosomes and the p arm of acrocentrics. The sequence homology at the rearrangement breakpoints appears to be, among others, the most frequent mechanism generating these variant chromosomes. The unbalanced carriers of this type of translocation may or may not display phenotypic abnormalities. With the aim to understand the causative mechanism, we revised all the ps–qs-chromosomes identified in five medical genetics laboratories, which used the same procedures for karyotype analysis, reporting 24 unrelated cases involving eight chromosomes. In conclusion, we observed three different scenarios: true translocation, benign variant and complex rearrangement. The detection of translocation partners is essential to evaluate possible euchromatic unbalances and to infer their effect on phenotype. Moreover, we emphasize the importance to perform both, molecular and conventional cytogenetics methods, to better understand the behavior of our genome.
Collapse
Affiliation(s)
- Serena Redaelli
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
| | - Donatella Conconi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
| | - Nicoletta Villa
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (N.V.); (E.S.); (F.C.)
| | - Elena Sala
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (N.V.); (E.S.); (F.C.)
| | - Francesca Crosti
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (N.V.); (E.S.); (F.C.)
| | - Cecilia Corti
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (C.C.); (I.C.); (M.G.); (M.P.R.)
| | - Ilaria Catusi
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (C.C.); (I.C.); (M.G.); (M.P.R.)
| | - Maria Garzo
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (C.C.); (I.C.); (M.G.); (M.P.R.)
| | - Lorenza Romitti
- Pathology and Cytogenetics Laboratory, Clinical Pathology Department, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy;
| | - Emanuela Martinoli
- Medical Genetics Laboratory, Medical Biotechnology and Translational Medicine Department, University of Milan, 20090 Milan, Italy; (E.M.); (P.R.)
| | - Antonella Patrizi
- Medical Cytogenetics Laboratory, Clinical Pathology Department, San Paolo Hospital, 20142 Milan, Italy; (A.P.); (R.M.)
| | - Roberta Malgara
- Medical Cytogenetics Laboratory, Clinical Pathology Department, San Paolo Hospital, 20142 Milan, Italy; (A.P.); (R.M.)
| | - Maria Paola Recalcati
- Medical Cytogenetics Laboratory, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy; (C.C.); (I.C.); (M.G.); (M.P.R.)
| | - Leda Dalprà
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
- Medical Genetics Laboratory, Clinical Pathology Department, S. Gerardo Hospital, 20900 Monza, Italy; (N.V.); (E.S.); (F.C.)
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
| | - Paola Riva
- Medical Genetics Laboratory, Medical Biotechnology and Translational Medicine Department, University of Milan, 20090 Milan, Italy; (E.M.); (P.R.)
| | - Gaia Roversi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
| | - Angela Bentivegna
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (D.C.); (L.D.); (M.L.); (G.R.)
- Correspondence: ; Tel.: +39-0264488133
| |
Collapse
|
|
32
|
Formation of human long intergenic non-coding RNA genes, pseudogenes, and protein genes: Ancestral sequences are key players. PLoS One 2020; 15:e0230236. [PMID: 32214344 PMCID: PMC7098633 DOI: 10.1371/journal.pone.0230236] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/25/2020] [Indexed: 12/20/2022] Open
Abstract
Pathways leading to formation of non-coding RNA and protein genes are varied and complex. We report finding a conserved repeat sequence present in human and chimpanzee genomes that appears to have originated from a common primate ancestor. This sequence is repeatedly copied in human chromosome 22 (chr22) low copy repeats (LCR22) or segmental duplications and forms twenty-one different genes, which include the human long intergenic non-coding RNA (lincRNA) family FAM230, a newly discovered lincRNA gene family termed conserved long intergenic non-coding RNAs (clincRNA), pseudogene families, as well as the gamma-glutamyltransferase (GGT) protein gene family and the RNA pseudogenes that originate from GGT sequences. Of particular interest are the GGT5 and USP18 protein genes that appear to have formed from an homologous repeat sequence that also forms the clincRNA gene family. The data point to ancestral DNA sequences, conserved through evolution and duplicated in humans by chromosomal repeat sequences that may serve as functional genomic elements in the development of diverse genes.
Collapse
|