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

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 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 3-5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic 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 resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each, <0.001). Predicted pathogenic 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 variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous and 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 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.