A nonsense mutation in COL4A4 gene causing isolated hematuria in either heterozygous or homozygous state

Cheng Yang, Yuan Song, Zhaowei Chen, Xiaohan Yuan, Xinhua Chen, Guohua Ding, Yang Guan, Mary McGrath, Chunhua Song, Yongqing Tong, Huiming Wang

Research output: Contribution to journalArticle

Abstract

Alport syndrome (AS) is a hereditary nephropathy characterized by glomerular basement membrane lesions. AS shows a relatively rare entity with autosomal dominant gene mutation (accounts for less than 5% of AS cases) and is widely believed to be a consequence of heterozygous variants in the COL4A3 and COL4A4 genes. Until now, there have been no reports of homozygous variants in genes in AS patients, and it is scarce to detect both homozygous and heterozygous variants in a single AS pedigree. We performed genetic analysis by exome sequencing (exome-seq) in a Chinese family with AS and found four individuals harboring the COL4A4 c.4599T > G variant, a novel COL4A4 nonsense mutation that gains stop codon and results in a truncated protein. The proband and her two siblings were determined to be heterozygous, whereas their mother was homozygous. The proband satisfied the criteria for the diagnosis of AS, which included clinical manifestations of microscopic hematuria and proteinuria, and pathological features of the glomerular basement membrane (GBM), including irregular thickening and splitting. However, the other three individuals who were homozygous or heterozygous for the variant exhibited mild clinical features with isolated microscopic hematuria. In summary, we identified a novel pathogenic variant in either the heterozygous or homozygous state of the COL4A4 gene in a Chinese family with AS. Our results also suggest that the severity of clinical manifestations may not be entirely attributed to by the COL4A4 genetic variant itself in patients.

Original languageEnglish (US)
Article number628
JournalFrontiers in Genetics
Volume10
Issue numberJUL
DOIs
StatePublished - Jan 1 2019

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Hereditary Nephritis
Nonsense Codon
Hematuria
Genes
Glomerular Basement Membrane
Exome
Dominant Genes
Terminator Codon
Pedigree
Proteinuria
Siblings
Mothers
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Yang, Cheng ; Song, Yuan ; Chen, Zhaowei ; Yuan, Xiaohan ; Chen, Xinhua ; Ding, Guohua ; Guan, Yang ; McGrath, Mary ; Song, Chunhua ; Tong, Yongqing ; Wang, Huiming. / A nonsense mutation in COL4A4 gene causing isolated hematuria in either heterozygous or homozygous state. In: Frontiers in Genetics. 2019 ; Vol. 10, No. JUL.
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title = "A nonsense mutation in COL4A4 gene causing isolated hematuria in either heterozygous or homozygous state",
abstract = "Alport syndrome (AS) is a hereditary nephropathy characterized by glomerular basement membrane lesions. AS shows a relatively rare entity with autosomal dominant gene mutation (accounts for less than 5{\%} of AS cases) and is widely believed to be a consequence of heterozygous variants in the COL4A3 and COL4A4 genes. Until now, there have been no reports of homozygous variants in genes in AS patients, and it is scarce to detect both homozygous and heterozygous variants in a single AS pedigree. We performed genetic analysis by exome sequencing (exome-seq) in a Chinese family with AS and found four individuals harboring the COL4A4 c.4599T > G variant, a novel COL4A4 nonsense mutation that gains stop codon and results in a truncated protein. The proband and her two siblings were determined to be heterozygous, whereas their mother was homozygous. The proband satisfied the criteria for the diagnosis of AS, which included clinical manifestations of microscopic hematuria and proteinuria, and pathological features of the glomerular basement membrane (GBM), including irregular thickening and splitting. However, the other three individuals who were homozygous or heterozygous for the variant exhibited mild clinical features with isolated microscopic hematuria. In summary, we identified a novel pathogenic variant in either the heterozygous or homozygous state of the COL4A4 gene in a Chinese family with AS. Our results also suggest that the severity of clinical manifestations may not be entirely attributed to by the COL4A4 genetic variant itself in patients.",
author = "Cheng Yang and Yuan Song and Zhaowei Chen and Xiaohan Yuan and Xinhua Chen and Guohua Ding and Yang Guan and Mary McGrath and Chunhua Song and Yongqing Tong and Huiming Wang",
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Yang, C, Song, Y, Chen, Z, Yuan, X, Chen, X, Ding, G, Guan, Y, McGrath, M, Song, C, Tong, Y & Wang, H 2019, 'A nonsense mutation in COL4A4 gene causing isolated hematuria in either heterozygous or homozygous state', Frontiers in Genetics, vol. 10, no. JUL, 628. https://doi.org/10.3389/fgene.2019.00628

A nonsense mutation in COL4A4 gene causing isolated hematuria in either heterozygous or homozygous state. / Yang, Cheng; Song, Yuan; Chen, Zhaowei; Yuan, Xiaohan; Chen, Xinhua; Ding, Guohua; Guan, Yang; McGrath, Mary; Song, Chunhua; Tong, Yongqing; Wang, Huiming.

In: Frontiers in Genetics, Vol. 10, No. JUL, 628, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Yang, Cheng

AU - Song, Yuan

AU - Chen, Zhaowei

AU - Yuan, Xiaohan

AU - Chen, Xinhua

AU - Ding, Guohua

AU - Guan, Yang

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AU - Song, Chunhua

AU - Tong, Yongqing

AU - Wang, Huiming

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