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Li Y, Dai L, Xu H, Huang J, Zhang J, Mei Z, Zhang R. Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants. Mol Genet Genomic Med 2024; 12:e2399. [PMID: 38439578 PMCID: PMC10912793 DOI: 10.1002/mgg3.2399] [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: 02/09/2023] [Revised: 08/24/2023] [Accepted: 02/05/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Nephronophthisis (NPHP) is a genetically heterogeneous disease that can lead to end-stage renal disease (ESRD) in children. The TTC21B variant is associated with NPHP12 and mainly characterized by cystic kidney disease, skeletal malformation, liver fibrosis, and retinopathy. Affected patients range from children to adults. Some patients experience ESRD in infancy or early childhood, but clinical reports on neonatal patients are rare. We report a case of NPHP12 in a premature infant and analyze its genetic etiology. METHODS Trio-whole exome sequencing analysis was performed on the patient and her parents; bioinformatics software was used to predict and analyze the hazards of the variants. Sanger sequencing was performed to verify variants. We calculated the free energy between mutant IFT139 and the IFT121-IFT122-IFT43 complex structure using molecular dynamics (MD). Finally, the clinical and genetic characteristics of patients with hotspot variant Cys518Arg were reviewed. RESULTS Genetic analysis revealed compound-heterozyous TTC21B variants in the patient, c.497delA (p.Lys166fs*36) and c.1552T>C (p.Cys518Arg). Her father and mother had heterozygous c.497delA (p.Lys166fs*36) and heterozygous c.1552T>C (p.Cys518Arg), respectively. Cys518Arg represents a hotspot variant, and the MD calculation results show that this can reduce the structural stability of the IFT121-IFT122-IFT139-IFT43 complex structure. A literature review showed that Cys518Arg might lead to the early occurrence of ESRD. CONCLUSIONS Compound-heterozygous TTC21B variants underlie the phenotype in this patient. Thus, Cys518Arg may be a hotspot variant in the Chinese population. Genetic testing should be recommended for NPHP in neonates and early infants.
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Affiliation(s)
- Yingying Li
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
| | - Liying Dai
- Department of NeonatologyAnhui Province Children's HospitalHefeiAnhuiChina
| | - Hong Xu
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
| | - Jin Huang
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
| | - Jinqiu Zhang
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
| | - Zhenzhu Mei
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
| | - Rui Zhang
- Department of NeonatologySuzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province)SuzhouAnhuiChina
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2
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Zhang H, Wang F, Xiao H. Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy. Nephrology (Carlton) 2023; 28:272-275. [PMID: 36878861 DOI: 10.1111/nep.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/19/2023] [Accepted: 02/20/2023] [Indexed: 03/08/2023]
Abstract
Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.
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Affiliation(s)
- Hongwen Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China
| | - Fang Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China
| | - Huijie Xiao
- Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China
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3
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Wang D, Chen X, Wen Q, Li Z, Chen W, Chen W, Wang X. A single heterozygous nonsense mutation in the TTC21B gene causes adult-onset nephronophthisis 12: A case report and review of literature. Mol Genet Genomic Med 2022; 10:e2076. [PMID: 36263627 PMCID: PMC9747551 DOI: 10.1002/mgg3.2076] [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: 06/16/2022] [Revised: 09/25/2022] [Accepted: 09/30/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Nephronophthisis type 12 (NPHP 12) is a rare cilia-related cystic kidney disease, caused by TTC21B mutation, mainly involving the kidneys, which generally occurs in children. Our study aimed to illustrate its clinical, pathological and genetic characteristics by reporting an adult-onset case of NPHP 12 caused by a single heterozygous nonsense mutation of TTC21B confirmed by renal histology and whole exome sequencing and reviewing related literature with a comparative analysis of the clinical features of each case. It will further increase the recognition of this rare kidney genetic disease, which sometimes can manifest as an adult disease. RESULTS A 33-years-old man showed a chronic disease course, and he exhibited slight renal dysfunction (CKD stage 3, eGFR = 49 ml/[min* 1.73 m2]) with renal tubular proteinuria, without any extrarenal manifestations, congenital malformation history of kidney disease, or family hereditary disease. Renal histological findings showed substantial interstitial fibrosis with some irregular and tortuous tubules with complex branches and segmental thickening and splitting of the tubular basement membrane. The patient was diagnosed with chronic interstitial nephritis for an unknown reason clinically. Further genetic analysis revealed a single heterozygous nonsense mutation in the TTC21B gene and NPHP 12 was diagnosed finally. CONCLUSION A single heterozygous mutation in the TTC21B gene may cause atypical NPHP12, which had a relatively later onset and milder clinical symptoms without developmental abnormalities. Therefore, for unexplained adult-onset chronic interstitial nephritis with unusual changes of renal tubules and interstitial fibrosis, even without a clear history of hereditary kidney disease, genetic testing is still recommended. The correct diagnosis of this rare adult-onset hereditary nephropathy can avoid unnecessary treatment.
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Affiliation(s)
- Dan Wang
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
| | - Xionghui Chen
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
| | - Qiong Wen
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
| | - Zhijian Li
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
| | - Wei Chen
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
| | - Wenfang Chen
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,Department of PathologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Xin Wang
- Department of NephrologyThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina,NHC Key Laboratory of Clinical Nephrology (Sun Yat‐sen University) and Guangdong Provincial Key Laboratory of NephrologySun Yat‐sen UniversityGuangzhouChina
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4
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Sambharia M, Rastogi P, Thomas CP. Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:377-398. [PMID: 35894442 PMCID: PMC9796580 DOI: 10.1002/ajmg.c.31990] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/31/2022] [Accepted: 06/30/2022] [Indexed: 01/29/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.
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Affiliation(s)
- Meenakshi Sambharia
- Division of Nephrology, Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
| | - Prerna Rastogi
- Department of PathologyUniversity of IowaIowa CityIowaUSA
| | - Christie P. Thomas
- Division of Nephrology, Department of Internal MedicineUniversity of IowaIowa CityIowaUSA,Department of PediatricsUniversity of IowaIowa CityIowaUSA,The Iowa Institute of Human GeneticsUniversity of IowaIowa CityIowaUSA,Medical ServiceVeterans Affairs Medical CenterIowa CityIowaUSA
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5
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Wells JR, Padua MB, Ware SM. The genetic landscape of cardiovascular left-right patterning defects. Curr Opin Genet Dev 2022; 75:101937. [PMID: 35777348 PMCID: PMC10698510 DOI: 10.1016/j.gde.2022.101937] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/11/2022] [Accepted: 05/19/2022] [Indexed: 11/26/2022]
Abstract
Heterotaxy is a disorder with complex congenital heart defects and diverse left-right (LR) patterning defects in other organ systems. Despite evidence suggesting a strong genetic component in heterotaxy, the majority of molecular causes remain unknown. Established genes often involve a ciliated, embryonic structure known as the left-right organizer (LRO). Herein, we focus on genetic discoveries in heterotaxy in the past two years. These include complex genetic architecture, novel mechanisms regulating cilia formation, and evidence for conservation of LR patterning between distant species. We feature new insights regarding established LR signaling pathways, bring attention to heterotaxy candidate genes in novel pathways, and provide an extensive overview of genes previously associated with laterality phenotypes in humans.
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Affiliation(s)
- John R Wells
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Maria B Padua
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Stephanie M Ware
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
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6
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A case of proliferative glomerulosclerosis with compound heterozygous TTC21B mutations. Clin Chim Acta 2022; 529:17-20. [DOI: 10.1016/j.cca.2022.01.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 11/22/2022]
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7
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Olinger E, Phakdeekitcharoen P, Caliskan Y, Orr S, Mabillard H, Pickles C, Tse Y, Wood K, Sayer JA. Biallelic variants in TTC21B as a rare cause of early-onset arterial hypertension and tubuloglomerular kidney disease. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:109-120. [PMID: 35289079 PMCID: PMC9314882 DOI: 10.1002/ajmg.c.31964] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/21/2022] [Accepted: 03/01/2022] [Indexed: 12/13/2022]
Abstract
Monogenic disorders of the kidney typically affect either the glomerular or tubulointerstitial compartment producing a distinct set of clinical phenotypes. Primary focal segmental glomerulosclerosis (FSGS), for instance, is characterized by glomerular scarring with proteinuria and hypertension while nephronophthisis (NPHP) is associated with interstitial fibrosis and tubular atrophy, salt wasting, and low- to normal blood pressure. For both diseases, an expanding number of non-overlapping genes with roles in glomerular filtration or primary cilium homeostasis, respectively, have been identified. TTC21B, encoding IFT139, however has been associated with disorders of both the glomerular and tubulointerstitial compartment, and linked with defective podocyte cytoskeleton and ciliary transport, respectively. Starting from a case report of extreme early-onset hypertension, proteinuria, and progressive kidney disease, as well as data from the Genomics England 100,000 Genomes Project, we illustrate here the difficulties in assigning this mixed phenotype to the correct genetic diagnosis. Careful literature review supports the notion that biallelic, often hypomorph, missense variants in TTC21B are commonly associated with early-onset hypertension and histological features of both FSGS and NPHP. Increased clinical recognition of this mixed glomerular and tubulointerstitial disease with often mild or absent features of a typical ciliopathy as well as inclusion of TTC21B on gene panels for early-onset arterial hypertension might shorten the diagnostic odyssey for patients affected by this rare tubuloglomerular kidney disease.
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Affiliation(s)
- Eric Olinger
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Pran Phakdeekitcharoen
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Yasar Caliskan
- Division of NephrologySaint Louis University Center for Abdominal TransplantationSt. LouisMissouriUSA
| | - Sarah Orr
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Holly Mabillard
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Charles Pickles
- Paediatric Nephrology, Great North Children's HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Yincent Tse
- Paediatric Nephrology, Great North Children's HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Katrina Wood
- Department of Cellular PathologyNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | | | - John A. Sayer
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK,Renal ServicesNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK,NIHR Newcastle Biomedical Research CentreNewcastle upon TyneUK
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8
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Gambino G, Catalano C, Marangoni M, Geers C, Moine AL, Boon N, Smits G, Ghisdal L. Case Report: Homozygous Pathogenic Variant P209L in the TTC21B Gene: A Rare Cause of End Stage Renal Disease and Biliary Cirrhosis Requiring Combined Liver-Kidney Transplantation. A Case Report and Literature Review. Front Med (Lausanne) 2021; 8:795216. [PMID: 34957165 PMCID: PMC8702958 DOI: 10.3389/fmed.2021.795216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/12/2021] [Indexed: 01/09/2023] Open
Abstract
Background: Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the TTC21B gene. Case Description: A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin. She presented with early onset of hypertension, pre-eclampsia, myopia and cirrhosis. Renal biopsy showed mild interstitial fibrosis, tubular atrophy, and moderate arteriosclerosis while liver pathology demonstrates grade B biliary cirrhosis. Family history revealed several cases of early-onset severe hypertension and one case of end-stage renal disease (ESRD) needing kidney transplantation at twenty years of age. Clinical exome sequencing showed homozygosis for the pathogenic variant c.626C>T (p.Pro209Leu) in the TTC21B gene. The patient underwent combined liver-renal transplantation with an excellent renal and hepatic graft outcome. Conclusions:TTC21B gene mutations can lead heterogeneous to clinical manifestations and represent an underappreciated cause of ESRD. The paradigm in diagnosis of CKD of early onset and/or of unknown origin is changing and genetic counseling should be performed in all patients and families that meet those criteria. Renal or combined liver-renal transplantation represents the best option for patients suffering from those diseases in terms of prognosis and quality of life.
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Affiliation(s)
- Giuseppe Gambino
- Department of Nephrology, Dialysis and Renal Transplantation, Erasmus Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Concetta Catalano
- Department of Nephrology, Dialysis and Renal Transplantation, Erasmus Erasme Hospital, Free University of Brussels, Brussels, Belgium
- *Correspondence: Concetta Catalano
| | - Martina Marangoni
- Department of Genetics, Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Caroline Geers
- Department of Nephropathology, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Department of Nephropathology, Brugmann University Hospital, Brussels, Belgium
| | - Alain Le Moine
- Department of Nephrology, Dialysis and Renal Transplantation, Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Nathalie Boon
- Department of Gastroenterology, Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Guillaume Smits
- Department of Genetics, Erasme Hospital, Free University of Brussels, Brussels, Belgium
| | - Lidia Ghisdal
- Department of Nephrology, Dialysis and Renal Transplantation, Erasmus Erasme Hospital, Free University of Brussels, Brussels, Belgium
- Department of Nephrology and Dialysis, Epicura Hospital, Saint-Ghislain, Belgium
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9
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Ben-Yosef T, Asia Batsir N, Ali Nasser T, Ehrenberg M. Retinal dystrophy as part of TTC21B-associated ciliopathy. Ophthalmic Genet 2021; 42:329-333. [PMID: 33599192 DOI: 10.1080/13816810.2021.1888131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Background: TCC21B is a ciliary protein. The most common phenotypic features associated with TCC21B biallelic mutations are nephronophthisis and skeletal abnormalities. To date, retinal dystrophy has been reported in only one patient.Materials and Methods: Clinical evaluation included best-corrected visual acuity, cycloplegic refraction, fundus examination, fundus photography, retinal imaging by optical coherence tomography, full-field electroretinography, multifocal electroretinography, and visual evoked potentials. Genetic analysis included Whole Exome Sequencing and confirmation of the identified mutations in the patient and his parents by PCR amplification and direct sequencing.Results: A ten-year-old Caucasian male presented with nephronophthisis, high myopia and nycatalopia. Best-corrected visual acuity was preserved to 20/20 in each eye with significant myopic correction. Visual fields were constricted. Optical coherence tomography confirmed the lack of outer retinal layers in the perifoveal area on both eyes. Electroretinography confirmed significant retinal dystrophy. Whole Exome Sequencing revealed compound heterozygous mutations in the TTC21B gene.Conclusions: TTC21B is associated with ciliopathy, but retinal dystrophy is a rare finding in these patients. We report retinal dystrophy secondary to TTC21B mutations, and provide for the first time detailed clinical information of the ophthalmic phenotype.
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Affiliation(s)
- Tamar Ben-Yosef
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Nurit Asia Batsir
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Tahleel Ali Nasser
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Miriam Ehrenberg
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Ophthalmology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
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10
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Strong A, Li D, Mentch F, Hakonarson H. A novel heterotaxy gene: Expansion of the phenotype of TTC21B-spectrum disease. Am J Med Genet A 2021; 185:1266-1269. [PMID: 33547761 PMCID: PMC9290470 DOI: 10.1002/ajmg.a.62093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/16/2020] [Accepted: 01/12/2021] [Indexed: 11/23/2022]
Abstract
TTC21B encodes the protein IFT139, a critical component of the retrograde transport system within the primary cilium. Biallelic, pathogenic TTC21B variants are associated with classic ciliopathy syndromes, including nephronophthisis, Jeune asphyxiating thoracic dystrophy, and Joubert Syndrome, with ciliopathy‐spectrum traits such as biliary dysgenesis, primary ciliary dyskinesia, and situs inversus, and also with focal segmental glomerulosclerosis. We report a 9‐year‐old male with focal segmental glomerulosclerosis requiring kidney transplant, primary ciliary dyskinesia, and biliary dysgenesis, found by research‐based exome sequencing to have biallelic pathogenic TTC21B variants. A sibling with isolated heterotaxy was found to harbor the same variants. This case highlights the phenotypic spectrum and unpredictable manifestations of TTC21B‐related disease, and also reports the first association between TTC21B and heterotaxy, nominating TTC21B as an important new heterotaxy gene.
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Affiliation(s)
- Alanna Strong
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Dong Li
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Frank Mentch
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Hakon Hakonarson
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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11
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Clinical and pathological features and varied mutational spectra of pathogenic genes in 55 Chinese patients with nephronophthisis. Clin Chim Acta 2020; 506:136-144. [PMID: 32173348 DOI: 10.1016/j.cca.2020.03.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/03/2020] [Accepted: 03/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Nephronophthisis (NPHP) is the most common genetic cause of end-stage renal disease (ESRD) in children. This study was performed to explore the pathogenic gene mutations and clinical and pathological features of Chinese patients with NPHP. METHODS Patients for whom causative mutations were not identified in our previous study, as well as those recruited later, were subjected to whole-exome next-generation sequencing (NGS) or the exome of 63 primary cilia disease genes. RESULTS We recruited 55 patients (27 boys and 28 girls) from 48 families, mainly from South China. We subjected 35 patients to NGS. Disease-causing mutations were revealed in seven more families (nine patients) by NGS. In total, disease-causing mutations were identified in 25 patients from 19 families, accounting for 39.6% (19/48) of all families, and novel mutation rate was 77.8% (35/45). NPHP1 and NPHP3 mutations were identified in 14.6% (7/48) and 12.5% (6/48) of all families, respectively. The patient with CEP83 mutations presented with prominent glomerular cysts and glomeruli dysplasia without extrarenal involvement. CONCLUSION A high novel mutation rate was identified, and disease-causing mutations of NPHP3 prevailed in this group of Chinese NPHP patients. This is the second report of a patient with CEP83 mutations.
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12
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Zhang HW, Su BG, Yao Y. OFD1 mutation induced renal failure and polycystic kidney disease in a pair of childhood male twins in China. World J Clin Cases 2020; 8:331-336. [PMID: 32047782 PMCID: PMC7000948 DOI: 10.12998/wjcc.v8.i2.331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/05/2019] [Accepted: 12/22/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Oral-facial-digital syndrome type 1 (OFD1) is a rare ciliopathy mainly with an X-linked dominant pattern of inheritance, which is caused by mutations in the OFD1 gene. The OFD1 protein is located within the centrosomes and basal bodies of the primary cilia. It is reported that approximately 15%–50% cases of OFD1 progress to end-stage renal disease (ESRD) following development of polycystic kidney diseases (PKD). Here we report a pair of childhood male twins who presented only renal failure and PKD caused by an OFD1 mutation in China.
CASE SUMMARY A pair of 14-year male twins were hospitalized with a complaint of abnormal renal function for nine days. They both complained of ankle pain for 3 mo vs 2 wk, respectively. They denied fever, abdominal pain, daytime or nighttime enuresis, urgency, dysuria, or gross hematuria. Laboratory tests at a local hospital showed renal failure (serum creatinine 485 μmol/L vs 442 μmol/L, blood urea nitrogen 14.7 mol/L vs 14.5 mol/L) and anemia (hemoglobin 88 g/L vs 98 g/L). The twins are monozygotic. There was no abnormal birth, past medical, or family history. Clinical data were analyzed and genetic analysis on PKD was carried out in the twins by next-generation sequencing. The results showed that the twins presented low-molecular-weight proteinuria, hyposthenuria, anemia, renal failure, and renal polycystic changes. Genetic tests showed that the twins both carried a hemizygous mutation in exon 19 c.2524G>A (p. G842R) of the OFD1 gene. Their mother heterozygously carried the same mutation as the twins but was without any phenotypes while their father was normal.
CONCLUSION We have reported a pair of childhood male twins with an OFD1 mutation who presented ESRD and PKD but without any other phenotypes of OFD1 in China.
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Affiliation(s)
- Hong-Wen Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
| | - Bai-Ge Su
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
| | - Yong Yao
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
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13
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Abo El Fotoh WMM, Al-Fiky AF. A Compound Heterozygous Mutation in the Ciliary Gene TTC21B Causes Nephronophthisis Type 12. J Pediatr Genet 2019; 9:198-202. [PMID: 32714622 DOI: 10.1055/s-0039-1700804] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 09/25/2019] [Indexed: 12/31/2022]
Abstract
Nephronophthisis (NPHP) is one of the renal ciliopathies and is also a cystic renal disorder with an autosomal recessive inheritance, which usually progresses to end-stage renal disease (ESRD). It affects children, adolescents, and young adults. In approximately 15% of cases, the features of a ciliopathy syndrome, which include liver fibrosis, skeletal anomalies, retinal abnormalities, and neurodevelopmental delay, will be present. We describe a case of a 2-year-old male child with ESRD on hemodialysis and a family record of a similar condition (his brother). The clinical features of this child are succinctly summarized. The genetic study was conducted using whole exome sequencing. TTC21B mutational variants were detected in our patient who exhibited nephrotic-range proteinuria, focal segmental glomerulosclerosis, and tubulointerstitial lesions that evolved to ESRD. Compound heterozygous mutations, c.626c > t (p.P209L) in exon 6 and c.450 g > a (p.W150Ter) in exon 5, were uncovered. These findings are in line with the description of autosomal recessive NPHP type 12. Both clinical and pathological diagnoses of NPHP are critical, bearing in mind ESRD as well as its related extrarenal defining features. Identification of the pathogenic variants in the TTC21B gene assisted in the successful proof of the clinical diagnosis NPHP12 as well as providing information for formal suitable prenatal counseling.
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Affiliation(s)
| | - Amira Fathy Al-Fiky
- Department of Pediatrics, Faculty of Medicine, Menoufia University Hospitals, Menoufia, Egypt
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Jian S, Wei QJ, Liu YT, Wang W, Zhou Y, Quan MY, He YY, Song HM, Wei M. [Clinical features and TTC21B genotype of a child with nephronophthisis type 12]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2019. [PMID: 31208513 DOI: 10.7499/j.issn.1008-8830.2019.06.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Nephronophthisis (NPHP) is a group of autosomal recessive tubulointerstitial cystic kidney disorders. This article reports a case of NPHP type 12 caused by TTC21B mutations. The girl had an insidious onset, with moderate proteinuria, renal dysfunction, stage 2 hypertension, situs inversus, and short phalanges when she visited the hospital for the first time at the age of 3 years and 6 months. The renal lesions progressed to end-stage renal disease (ESRD) before she was 4 years old. Urine protein electrophoresis showed glomerular proteinuria. There were significant increases in urinary β2-microglobulin and α1-microglobulin. Gene detection revealed two compound heterozygous mutations, c.1552T>C (p.C518R) and c.752T>G (p.M251R), in the TTC21B gene, which came from her father and mother respectively. The c.752T>G mutation was a novel mutation. It is concluded that besides typical tubular changes of NPHP, marked glomerular damage is also observed in patients with TTC21B gene mutations.
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Affiliation(s)
- Shan Jian
- Department of Pediatrics, Peking Union Medical College Hospital, Beijing 100730, China.
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Chen L, Wei Y, Chi W, Fang D, Jiang X, Zhang S. Potential Mutations in Chinese Pathologic Myopic Patients and Contributions to Phenotype. Curr Mol Med 2019; 18:689-697. [PMID: 30747064 PMCID: PMC6635424 DOI: 10.2174/1566524019666190211120016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 01/07/2019] [Accepted: 01/07/2019] [Indexed: 12/02/2022]
Abstract
Purpose Pathologic myopia is a leading cause of visual impairment in East Asia. The aim of this study was to investigate the potential mutations in Chinese pathologic myopic patients and to analyze the correlations between genotype and clinical phenotype. Method One hundred and three patients with pathologic myopia and one hundred and nine unrelated healthy controls were recruited from Zhongshan Ophthalmic Center. Detailed clinical data, including ultra-widefield retinal images, measurements of best-corrected visual acuity, axial length, refractive error and ophthalmic examination results, were obtained. Blood samples were collected for high-throughput DNA targeted sequencing. Based on the screening results, phenotype-genotype correlations were analyzed. Results The study included 196 eyes of 103 patients (36 men and 67 women) with an average age of 52.19 (38.92 – 65.46) years, an average refractive error of -11.80 D (-16.38 – -7.22) and a mean axial length of 28.26 mm (25.79 – 30.73). The patients were subdivided into three groups: myopic chorioretinal atrophy (190 eyes of 101 patients), myopic choroidal neovascularization (17 eyes of 15 patients), and myopic traction retinopathy (71 eyes of 61 patients). Systematic analysis of variants in the 255 genes revealed six potential pathogenic mutations: PEX7, OCA2, LRP5 (rs545382, c.1647T>C), TSPAN12 (rs41623, c.765G>T), RDH5 (rs3138142, c.423C>T) and TTC21B (rs80225158, c.2385G>C). OCA2 mutations were primarily observed in patients with myopic traction maculopathy. Conclusion Genetic alterations contribute to various clinical characteristics in Chinese pathologic myopic patients. The study may provide new insights into the etiology of pathologic myopia and potential targets for therapeutic interventions.
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Affiliation(s)
- L Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.,Shenzhen Eye Hospital, Shenzhen Eye Institute, Jinan University, Shenzhen, China
| | - Y Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - W Chi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - D Fang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - X Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - S Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Zhang H, Wang F, Xiao H, Yao Y. The ratio of urinary α1-microglobulin to microalbumin can be used as a diagnostic criterion for tubuloproteinuria. Intractable Rare Dis Res 2018; 7:46-50. [PMID: 29552446 PMCID: PMC5849625 DOI: 10.5582/irdr.2017.01079] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Low-molecular-weight proteinuria is one of the characteristic clinical manifestations of renal tubular and interstitial diseases. Low-molecular-weight proteinuria is defined as excessive urinary loss of α1-microglobulin, β2-microglobulin, or other low-molecular-weight plasma proteins. The current study examined the ratio of urinary α1-microglobulin to microalbumin in 24 Chinese pediatric patients with renal tubular and interstitial diseases, including 10 patients with Dent disease, 2 patients with Lowe syndrome, 6 patients with acute tubulointerstitial nephritis (ATIN), 4 patients with acute tubulointerstitial nephritis with uveitis syndrome (TINU), and 2 patients with nephronophthisis (NPHP). Patients with steroid-sensitive nephrotic syndrome, IgA nephropathy, Henoch-Schonlein purpura nephritis, or lupus nephritis served as control groups. In all of the patients with tubular and interstitial disease, urinary α1-microglobin increased 10-300-fold above the upper limit of the normal range, the ratio of urinary α1-microglobulin to microalbumin was greater than 1, and the percentage of low-molecular-weight plasma proteins (LMWP) in urine was greater than 50% according to urine protein electrophoresis. There was close correlation between the ratio of urinary α1-microglobulin to microalbumin and the percentage of LMWP in urine according to urine protein electrophoresis (r = 0.797, p = 0.000). We suggested firstly that the ratio of urinary α1-microglobulin to microalbumin, greater than 1, can be used as a diagnostic criterion for tubuloproteinuria.
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Affiliation(s)
- Hongwen Zhang
- Department of Pediatric, Peking University First Hospital, Beijing, China
| | - Fang Wang
- Department of Pediatric, Peking University First Hospital, Beijing, China
| | - Huijie Xiao
- Department of Pediatric, Peking University First Hospital, Beijing, China
| | - Yong Yao
- Department of Pediatric, Peking University First Hospital, Beijing, China
- Address correspondence to: Dr. Yong Yao, Department of Pediatric, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China. E-mail:
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