ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease

AbstractWilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase geneATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency ofATP7B variants in a genomic sequence database. A catalogue of WD-associatedATP7B variants was constructed, and then, frequency information for these was extracted from the gnomAD data set. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associatedATP7B variants were identified in the gnomAD data set, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associatedATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD....
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research