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Prevalence Estimates of Predicted Pathogenic COL4A3-COL4A5 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 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 alpha3-alpha5 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.

Type Journal
ISBN 1533-3450 (Electronic) 1046-6673 (Linking)
Authors Gibson, J.; Fieldhouse, R.; Chan, M. M. Y.; Sadeghi-Alavijeh, O.; Burnett, L.; Izzi, V.; Persikov, A. V.; Gale, D. P.; Storey, H.; Savige, J.; Genomics England Research, Consortium
Published Date 2021-09-30
Published Volume 32
Published Issue 9
Published Pages 2273-2290
Status Published in-print
DOI 10.1681/ASN.2020071065
URL link to publisher's version