The Phenotypic Spectrum of COL4A3 Heterozygotes.

Alport Syndrome (AS) is the second most common genetic cause of end-stage kidney disease (ESKD), yet little is known about the penetrance and phenotypic spectrum of genetically-determined Autosomal Dominant AS. Using an unselected health system-based cohort, we compared individuals heterozygous for likely pathogenic or pathogenic variants in COL4A3 to a propensity score-matched control group and demonstrate increased risks of hematuria, albuminuria, and ESKD. Risks of kidney disease phenotypes were markedly elevated for missense glycine variants in the collagenous domain and moderately elevated for those with PTVs, compared to controls. The vast majority had not been diagnosed with AS and less than a third ever received albuminuria testing, suggesting opportunities to improve management by early genetic diagnosis.