Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries.

Background & aims: Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations.

Methods: Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records.

Results: The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients.

Conclusions: The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.