Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes.

Truncating and NC1 missense variants in COL4A4 heterozygotes are strongly linked to hematuria and proteinuria, while the same variant classes in COL4A3 show attenuated or absent associations.

• Why it matters: Monoallelic COL4A3 and COL4A4 pathogenic variants are rare, but population-scale evidence has been lacking on whether paralogous genes confer equivalent risk for the same variant classes.
• What they did: Using whole-genome sequencing from UK Biobank (~500,000) and replication in All of Us (~414,000), the study ran per-variant association tests, gene-based collapsing analyses, and PheWAS across hematuria, proteinuria, and chronic kidney disease.
• The result: It found 64 COL4A3 and 92 COL4A4 rare variants associated with hematuria or proteinuria, with glycine substitutions showing similar risks, but truncating and NC1 variants differing sharply between genes and replicated in All of Us.

AI summary of the abstract · may contain errors · not medical advice · read the paper.