Gibson, J;
Fieldhouse, R;
Chan, MMY;
Sadeghi-Alavijeh, O;
Burnett, L;
Izzi, V;
Persikov, AV;
... Savige, J; + view all
(2021)
Prevalence estimates of predicted pathogenic col4a3-col4a5 variants in a population sequencing database and their implications for alport syndrome.
Journal of the American Society of Nephrology
, 32
(9)
pp. 2273-2290.
10.1681/ASN.2020071065.
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Abstract
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 pathogenicCOL4A3-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 IVa3-a5 position 1Gly 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 substitutionswere confirmed to be associated with hematuria (for each, P<0.001). Predicted pathogenicCOL4A5 variantswere found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants inEuropeans.MostCOL4A5 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 forAlport syndrome are suggested by the frequencies of predicted pathogenicCOL4A3-COL4A5 variants,butmustbeadjustedfor thediseasepenetranceof individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.
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