Background: The prevalence of Alport syndrome varies from one in 5,000 to one in 53,000. 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 that considered collagen IV α3-α5 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 associated with haematuria (p each <0.0001). Predicted pathogenic COL4A5 variants were found in at least one in 2,320 individuals. p.(Gly624Asp), represented nearly half (16/33, 48%) the variants in Europeans. Most COL4A5 variants (54/59, 92%) had a biochemical feature that potentially mitigated clinical impact. 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 biopsies. 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, as well as the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.
Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3–COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
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