Prevalence Estimates of Predicted Pathogenic COL4A3–COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome

BACKGROUND: variants in sequencing databases of populations without known kidney disease. METHODS: variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants. RESULTS: variants affected one in 106 of the population, consistent with the finding of thin basement membrane nephropathy in normal donor kidney biopsy specimens. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals, and digenic variants in at least one in 44,793. CONCLUSIONS: variants, but must be adjusted for the disease penetrance of individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.