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

Abstract

Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. 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 of ATP7B variants in a genomic sequence database. A catalogue of WDassociated ATP7B variants was constructed and then frequency information for these was extracted from the gnomAD dataset. 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-associated ATP7B variants were identified in the gnomAD dataset, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B 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. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.

Estimating the clinical prevalence of Wilson’s disease in the UK

“… 18 , 25 Several reasons are likely to contribute to this difference including the presence of more than 600 pathogenic or likely pathogenic variants in ATP7B, 10 difference in the severity of certain variants e.g. truncating variants that lead to a significant decrease in the protein vs. missense changes, and also the combination of variants in either homozygous or compound-heterozygous states, 26 new classification criteria for assessing pathogenicity of variants, 27 variation in penetrance of certain variants, 11 the potential for epigenetic mechanisms of gene expression regulation causing clinical disease 28 and the likeliness of undiagnosed cases being missed in clinical prevalence studies. 29 …”

“… 10 Variable penetrance of disease-causing mutations is being considered a contributor to the poor correlation between the genetic and clinical prevalence. 11 Further, the identification of pathogenic mutations based on algorithmic predictions 10 may also contribute the discrepancy through mislabelling of benign mutations as pathogenic.…”

Movement Disorders and Liver Disease

“…Age and sex are important determinants of disease phenotype, while ATP7B genotype is an important determinant of penetrance. 5,6 Hepatic manifestations often predominate in childhood, while neurological presentations occur more frequently in adolescence/ early adulthood. 4,5 Hepatic manifestations of WD are protean, existing along a spectrum ranging from completely undetectable through varying degrees of chronic active hepatitis, progressing if untreated to cirrhosis and decompensated liver disease.…”

“…Age and sex are important determinants of disease phenotype, while ATP7B genotype is an important determinant of penetrance. 5 , 6 Hepatic manifestations often predominate in childhood, while neurological presentations occur more frequently in adolescence/early adulthood. 4 , 5 …”

Clinical and genetic characterization of a large cohort of patients with Wilson’s disease in China

“…WD is characterized by hepatic or/and neurological symptoms, corneal Kayser–Fleischer’s (K–F) rings, low ceruloplasmin levels, and elevated 24-h urinary copper levels [ 4 ]. The clinically estimated prevalence of WD is 1/30,000 to 1/50,000 in the USA, Europe, and Asia, which is lower than the genetic prevalence due to factors such as above-zero onset age, shortened life expectancy, delayed diagnosis, overlooked cases, and low penetrance of some ATP7B variants [ 5 , 6 ].…”