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Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome

BACKGROUND: Alport syndrome is an inherited renal disease caused by mutations in COL4A3, COL4A4, or COL4A5 genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in COL4A3 or COL4A4 genes in X‐linked...

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Autores principales: Zhang, Yanqin, Ding, Jie, Zhang, Hongwen, Yao, Yong, Xiao, Huijie, Wang, Suxia, Wang, Fang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503168/
https://www.ncbi.nlm.nih.gov/pubmed/30883042
http://dx.doi.org/10.1002/mgg3.647
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author Zhang, Yanqin
Ding, Jie
Zhang, Hongwen
Yao, Yong
Xiao, Huijie
Wang, Suxia
Wang, Fang
author_facet Zhang, Yanqin
Ding, Jie
Zhang, Hongwen
Yao, Yong
Xiao, Huijie
Wang, Suxia
Wang, Fang
author_sort Zhang, Yanqin
collection PubMed
description BACKGROUND: Alport syndrome is an inherited renal disease caused by mutations in COL4A3, COL4A4, or COL4A5 genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in COL4A3 or COL4A4 genes in X‐linked Alport syndrome (XLAS) patients is unclear. METHODS: Using targeted next‐generation sequencing, six unrelated Chinese children were identified to have a combination of a pathogenic variant in COL4A5 and a heterozygous mutation in COL4A3 or COL4A4. They were three males and three females. Another three XLAS males each with only one pathogenic variant in COL4A5 were included. The clinical data were analyzed and compared between the males in two groups (group 1, males with a pathogenic variant in COL4A5 and a heterozygous pathogenic variant in COL4A3 or COL4A4; group 2, males with only one pathogenic variant in COL4A5). RESULTS: Patients with XLAS who also had heterozygous pathogenic COL4A3 or COL4A4 variants accounted for 1% of Alport syndrome. In this study, three children showed coexisting pathogenic variants in COL4A5 and COL4A3. Two children showed pathogenic variants in COL4A5 and COL4A4. One child had pathogenic variants in the three COL4A3‐5 genes, in which the pathogenic variant in COL4A5 was de novo and the pathogenic variants in COL4A4 and COL4A3 were inherited independently (in trans). The site and type of mutations in COL4A5 were similar between the two groups. It was revealed that males in group 1 presented more severe proteinuria than males in group 2 (p < 0.05). CONCLUSION: The present study provides further evidence for complicated genotype in Alport syndrome. For the first time, we reported a case with three pathogenic variants in COL4A5, COL4A3, and COL4A4 genes. Moreover, we found that heterozygous pathogenic COL4A3 or COL4A4 variants are likely to make XLAS disease more serious.
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spelling pubmed-65031682019-05-10 Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome Zhang, Yanqin Ding, Jie Zhang, Hongwen Yao, Yong Xiao, Huijie Wang, Suxia Wang, Fang Mol Genet Genomic Med Original Articles BACKGROUND: Alport syndrome is an inherited renal disease caused by mutations in COL4A3, COL4A4, or COL4A5 genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in COL4A3 or COL4A4 genes in X‐linked Alport syndrome (XLAS) patients is unclear. METHODS: Using targeted next‐generation sequencing, six unrelated Chinese children were identified to have a combination of a pathogenic variant in COL4A5 and a heterozygous mutation in COL4A3 or COL4A4. They were three males and three females. Another three XLAS males each with only one pathogenic variant in COL4A5 were included. The clinical data were analyzed and compared between the males in two groups (group 1, males with a pathogenic variant in COL4A5 and a heterozygous pathogenic variant in COL4A3 or COL4A4; group 2, males with only one pathogenic variant in COL4A5). RESULTS: Patients with XLAS who also had heterozygous pathogenic COL4A3 or COL4A4 variants accounted for 1% of Alport syndrome. In this study, three children showed coexisting pathogenic variants in COL4A5 and COL4A3. Two children showed pathogenic variants in COL4A5 and COL4A4. One child had pathogenic variants in the three COL4A3‐5 genes, in which the pathogenic variant in COL4A5 was de novo and the pathogenic variants in COL4A4 and COL4A3 were inherited independently (in trans). The site and type of mutations in COL4A5 were similar between the two groups. It was revealed that males in group 1 presented more severe proteinuria than males in group 2 (p < 0.05). CONCLUSION: The present study provides further evidence for complicated genotype in Alport syndrome. For the first time, we reported a case with three pathogenic variants in COL4A5, COL4A3, and COL4A4 genes. Moreover, we found that heterozygous pathogenic COL4A3 or COL4A4 variants are likely to make XLAS disease more serious. John Wiley and Sons Inc. 2019-03-18 /pmc/articles/PMC6503168/ /pubmed/30883042 http://dx.doi.org/10.1002/mgg3.647 Text en © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhang, Yanqin
Ding, Jie
Zhang, Hongwen
Yao, Yong
Xiao, Huijie
Wang, Suxia
Wang, Fang
Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title_full Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title_fullStr Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title_full_unstemmed Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title_short Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome
title_sort effect of heterozygous pathogenic col4a3 or col4a4 variants on patients with x‐linked alport syndrome
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503168/
https://www.ncbi.nlm.nih.gov/pubmed/30883042
http://dx.doi.org/10.1002/mgg3.647
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