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Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome

Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR), or autosomal dominant (AD) disease, where pathogenic COL4A3 – COL4A5 variants affect the basement membrane collagen IV α3α4α5 network. About 50% of pathogenic variants in each gene (major rearrangements and large deletions i...

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Autores principales: Savige, Judy, Huang, Mary, Croos Dabrera, Marina Shenelli, Shukla, Krushnam, Gibson, Joel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120524/
https://www.ncbi.nlm.nih.gov/pubmed/35602506
http://dx.doi.org/10.3389/fmed.2022.865034
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author Savige, Judy
Huang, Mary
Croos Dabrera, Marina Shenelli
Shukla, Krushnam
Gibson, Joel
author_facet Savige, Judy
Huang, Mary
Croos Dabrera, Marina Shenelli
Shukla, Krushnam
Gibson, Joel
author_sort Savige, Judy
collection PubMed
description Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR), or autosomal dominant (AD) disease, where pathogenic COL4A3 – COL4A5 variants affect the basement membrane collagen IV α3α4α5 network. About 50% of pathogenic variants in each gene (major rearrangements and large deletions in 15%, truncating variants in 20%, splicing changes in 15%) are associated with “severe” disease with earlier onset kidney failure, and hearing loss and ocular abnormalities in males with XL inheritance and in males and females with AR disease. Severe variants are also associated with early proteinuria which is itself a risk factor for kidney failure. The other half of pathogenic variants are missense changes which are mainly Gly substitutions. These are generally associated with later onset kidney failure, hearing loss, and less often with major ocular abnormalities. Further determinants of severity for missense variants for XL disease in males, and in AD disease, include Gly versus non-Gly substitutions; increased distance from a non-collagenous interruption or terminus; and Gly substitutions with a more (Arg, Glu, Asp, Val, and Trp) or less disruptive (Ala, Ser, and Cys) residue. Understanding genotype-phenotype correlations in Alport syndrome is important because they help predict the likely age at kidney failure, and the need for early and aggressive management with renin-angiotensin system blockade and other therapies. Genotype-phenotype correlations also help standardize patients with Alport syndrome undergoing trials of clinical treatment. It is unclear whether severe variants predispose more often to kidney cysts or coincidental IgA glomerulonephritis which are recognized increasingly in COL4A3-, COL4A4 - and COL4A5-associated disease.
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spelling pubmed-91205242022-05-21 Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome Savige, Judy Huang, Mary Croos Dabrera, Marina Shenelli Shukla, Krushnam Gibson, Joel Front Med (Lausanne) Medicine Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR), or autosomal dominant (AD) disease, where pathogenic COL4A3 – COL4A5 variants affect the basement membrane collagen IV α3α4α5 network. About 50% of pathogenic variants in each gene (major rearrangements and large deletions in 15%, truncating variants in 20%, splicing changes in 15%) are associated with “severe” disease with earlier onset kidney failure, and hearing loss and ocular abnormalities in males with XL inheritance and in males and females with AR disease. Severe variants are also associated with early proteinuria which is itself a risk factor for kidney failure. The other half of pathogenic variants are missense changes which are mainly Gly substitutions. These are generally associated with later onset kidney failure, hearing loss, and less often with major ocular abnormalities. Further determinants of severity for missense variants for XL disease in males, and in AD disease, include Gly versus non-Gly substitutions; increased distance from a non-collagenous interruption or terminus; and Gly substitutions with a more (Arg, Glu, Asp, Val, and Trp) or less disruptive (Ala, Ser, and Cys) residue. Understanding genotype-phenotype correlations in Alport syndrome is important because they help predict the likely age at kidney failure, and the need for early and aggressive management with renin-angiotensin system blockade and other therapies. Genotype-phenotype correlations also help standardize patients with Alport syndrome undergoing trials of clinical treatment. It is unclear whether severe variants predispose more often to kidney cysts or coincidental IgA glomerulonephritis which are recognized increasingly in COL4A3-, COL4A4 - and COL4A5-associated disease. Frontiers Media S.A. 2022-05-06 /pmc/articles/PMC9120524/ /pubmed/35602506 http://dx.doi.org/10.3389/fmed.2022.865034 Text en Copyright © 2022 Savige, Huang, Croos Dabrera, Shukla and Gibson. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Savige, Judy
Huang, Mary
Croos Dabrera, Marina Shenelli
Shukla, Krushnam
Gibson, Joel
Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title_full Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title_fullStr Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title_full_unstemmed Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title_short Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome
title_sort genotype-phenotype correlations for pathogenic col4a3–col4a5 variants in x-linked, autosomal recessive, and autosomal dominant alport syndrome
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120524/
https://www.ncbi.nlm.nih.gov/pubmed/35602506
http://dx.doi.org/10.3389/fmed.2022.865034
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