AUTHOR=Savige Judy , Huang Mary , Croos Dabrera Marina Shenelli , Shukla Krushnam , Gibson Joel 

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

JOURNAL=Frontiers in Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.865034

DOI=10.3389/fmed.2022.865034

ISSN=2296-858X

ABSTRACT=Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR) or autosomal dominant (AD) disease, where pathogenic COL4A3 – 5 variants affect the basement membrane collagen IV 345 network. 

About 50% of pathogenic variants in each gene (major rearrangements, 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 50% 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, Trp) or less disruptive (Ala, Ser, 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 standardise 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 recognised increasingly in COL4A3 – COL4A5-associated disease.