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

Significance Statement The population frequencies of Alport syndrome vary greatly in different reports. This study examined a population sequencing database of individuals not known to have kidney disease using filtering steps corresponding to the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria for “predicted pathogenic” variants in COL4A3–COL4A5 , which considered collagen chain position 1 Gly residues “critical domains.” Predicted pathogenic COL4A5 variants occurred in at least one in 2320 individuals. Heterozygous COL4A3 or COL4A4 variants affected one in 106; compound heterozygous COL4A3 or COL4A4 variants affected one in 88,866. The actual prevalences are even greater because they also include already diagnosed disease and other variants not examined here. The high frequency of predicted pathogenic COL4A3 – COL4A5 variants suggests that other genetic and environmental factors mitigate the corresponding clinical manifestations of disease. Background The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic COL4A3–COL4A5 variants in sequencing databases of populations without known kidney disease. Methods Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria, which considered collagen IV α 3– α 5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3–COL4A5 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 COL4A3–COL4A5 variants resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each, P <0.001). Predicted pathogenic COL4A5 variants were found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants in Europeans. Most COL4A5 variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous COL4A3 and COL4A4 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 The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3–COL4A5 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