Abstract
Wilson disease (WD) is a genetic disorder of copper metabolism. It can present with hepatic and neurological symptoms, due to copper accumulation in the liver and brain. WD is caused by compound heterozygosity or homozygosity for mutations in the copper transporting P-type ATPase gene ATP7B. Over 700 ATP7B genetic variants have been associated with WD. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some studies have estimated much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD by determining the frequency and evaluating the pathogenicity of ATP7B variants in a genomic sequence database. A catalogue of 732 WD-associated ATP7B variants was constructed using data from the WD Mutation Database and a literature review. A total of 231 WD-associated ATP7B variants were present in the gnomAD dataset giving an estimated population prevalence of around 1 in 2400 with a carrier rate of 1 in 25. Pathogenicity of the 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. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimates showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Conclusion: We have calculated the prevalence of WD based on genomic sequencing data and our results highlight the importance of assessing penetrance when assigning causality to genetic variants. The high frequency of low penetrant ATP7B variants raises the possibility that these variants could contribute to abnormalities in copper homeostasis that do not manifest in a clear WD phenotype and diagnosis.
Author Summary Wilson disease is a genetic disorder that causes copper accumulation in the liver and brain. It is caused by mutations in the ATP7B gene that encodes a protein involved in transporting copper across cell membranes. We used genomic sequencing data from more than 120,000 people from 8 global populations to estimate the prevalence of mutations that cause Wilson disease. From these data we calculated the predicted prevalence of Wilson disease and found that it is much higher than traditional estimates. Further analysis revealed that this high prevalence is likely due to several mutations that are too common to be a major cause of the disease and may only have mild effects on ATP7B protein function. After taking these mild mutations into account in our estimates of disease prevalence, we predict that Wilson disease has a population prevalence of around 1 in 20,000 with higher rates in East Asian and Ashkenazi Jewish populations. Our results suggest that some mutations in ATP7B may cause milder forms of Wilson disease.