A disease-causing variant of COL4A5 in a Chinese family with Alport syndrome: a case series

Jing Wu,Tomohiko Yamamura,Jun Zhang,Kandai Nozu,Li Liu,Masafumi Matsuo,Bo Zhang,Jinghong Zhao

doi:10.1186/s12882-021-02585-7

Jing Wu, Tomohiko Yamamura + Show 6 more

Open Access

https://doi.org/10.1186/s12882-021-02585-7

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Abstract

BackgroundAlport syndrome (AS), which is a rare hereditary disease caused by mutations of genes including COL4A3, COL4A4 and COL4A5, has a wide spectrum of phenotypes. Most disease-causing variants of AS are located in the exons or the conservative splicing sites of these genes, while little is known about the intronic disease-causing variants.MethodsA Chinese AS family was recruited in this study. All the clinical data of AS patient were collected from medical records. After pedigree analysis, the pathogenic variants were studied by the whole exome sequencing (WES). Minigene assay and in vivo RT-PCR analysis were performed to validate the functions of the variants.ResultsRenal biopsy showed a typical histopathology changes of AS. WES revealed compound heterozygous substitution, NM_033380 c.991–14(IVS17) A > G, in the intron 17 of the COL4A5 gene, which were confirmed by Sanger sequencing. Moreover, the variant was co-segregated with the phenotype in this family. Minigene assay in cultured cell lines showed that a splicing error was induced by this intronic variant, which further confirmed by in vivo RT-PCR analysis.ConclusionA novel intronic disease-causing variant in COL4A5 gene was identified by WES, which was the molecular pathogenic basis of AS.

Highlights

Alport syndrome (AS), which is a rare hereditary disease caused by mutations of genes including COL4A3, COL4A4 and COL4A5, has a wide spectrum of phenotypes
We reported a functional intronic variant in a Chinese family. a functional splicing assay using
No other parameters were revealed by other laboratory tests including blood routine tests, serum chemistry and immunology

Summary

Introduction

Alport syndrome (AS), which is a rare hereditary disease caused by mutations of genes including COL4A3, COL4A4 and COL4A5, has a wide spectrum of phenotypes. Alport syndrome (AS) is a hereditary nephropathy, whose phenotypes ranged from isolated hematuria with a non-progressive course to progressive renal disease with extrarenal abnormalities [1,2,3]. The clinical diagnose of AS is mainly based on clinical manifestations and renal histopathology. Due to the large sizes of these genes and the absence of mutation hot spots, PCR-based screening of the variants of AS patients is much complicated and time-consuming [4, 5]. With the progress in next-generation sequencing (NGS), a strategy by utilizing targeted capture to analyze COL4A3, COL4A4, and COL4A5 is much powerful [6]. With the expense of whole exon sequencing (WES) goes

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