Whole exome sequencing reveals novel COL4A3 and COL4A4mutations and resolves diagnosis in Chinese families with kidney diseaseReport as inadecuate




Whole exome sequencing reveals novel COL4A3 and COL4A4mutations and resolves diagnosis in Chinese families with kidney disease - Download this document for free, or read online. Document in PDF available to download.

BMC Nephrology

, 15:175

Genetics

Abstract

BackgroundCollagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome AS, are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features.

MethodsThree families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing WES was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing.

ResultsWe identified COL4A4 missense variants c.G2636A p.Gly879Glu and c.C4715T p.Pro1572Leu in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A p.Gly997Glu was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease ESRD. In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation c.687 + 1G > A. None of these variants were detected among 100 healthy Chinese individuals.

ConclusionWES identified 2 novel and 2 known pathogenic COL4A3-COL4A4-COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical-histological findings, allowing appropriate counselling and treatment advice to be given.

KeywordsCollagen IV-related nephropathies Whole exome sequencing Novel mutation Misdiagnosis Electronic supplementary materialThe online version of this article doi:10.1186-1471-2369-15-175 contains supplementary material, which is available to authorized users.

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Author: Fujun Lin - Fan Bian - Jun Zou - Xiangru Wu - Jianping Shan - Wei Lu - Yao Yao - Gengru Jiang - Daniel Philip Gale

Source: https://link.springer.com/







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