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

COL4A3, COL4A4

Rare heterozygous COL4A3 and COL4A4 variants: comparable risk for glycine substitutions in the collagenous domain, but truncating and NC1-domain missense variants strongly associated with disease for COL4A4 and weakly or not for COL4A3

Monoallelic pathogenic or likely pathogenic COL4A3 and COL4A4 variants occur in approximately 1 in 106 individuals. Using UK Biobank genomes (about 500,000 participants), with replication in All of Us (about 414,000), the authors performed per-variant association testing, gene-based collapsing analyses and PheWAS across hematuria, proteinuria and chronic kidney disease. They identify 64 COL4A3 and 92 COL4A4 rare variants significantly associated with hematuria or proteinuria. Glycine substitutions in the collagenous domain confer similar risks in both genes, but truncating and NC1-domain missense variants, strongly associated with disease in COL4A4 heterozygotes, show substantially attenuated or absent associations in COL4A3 heterozygotes despite comparable allele frequencies and predicted pathogenicity scores. The COL4A3-COL4A4 locus emerges as the dominant genetic determinant of hematuria, driven by the aggregate effect of rare coding variants, with no independent common-variant or trans-acting modifier effect.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A result directly useful for interpretation: a heterozygous truncating or NC1 missense variant does not carry the same weight in COL4A3 as in COL4A4, and the authors recommend that gene identity, not variant class alone, should guide risk stratification, variant interpretation and genetic counseling. Per-variant associations provide quantitative support for classifying variants in both genes. Limitation: these population data measure an average risk per variant class and do not, on their own, predict the renal course of an individual carrier.

Analysis by Dr Thibaut Benquey