A genetic study of Wilson’s disease in the United Kingdom

Abstract

Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

Epidemiology, diagnosis, and treatment of Wilson's disease

“…Sequencing of ATP7B in 1,000 control participants in the UK allowed the frequency of an individual carrying two mutant ATP7B alleles to be estimated at 1/7,026 (17). The most common mutation in Europe and North America is p.H1069Q (1).…”

“…The prevalence of WD is higher in China than in the West (18). Since the first estimate of WD in 1968, considerable progress has been made in China.…”

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

“…WD is an eminently treatable monogenic disease [5]. Its main symptoms include hepatic and neurological disorders ranging from mild abnormities to aggravated progressions [26,27].…”

“…3,000 in East Asia and 1: 7,000 in the United Kingdom [3][4][5]. Typical features of WD include hepatic dysfunction, neurological disorders, psychiatric symptoms, corneal Kayser-Fleischer (K-F) rings, and low serum ceruloplasmin levels [6][7][8].…”

Bioavailable Trace Metals in Neurological Diseases

“…Clinical prevalence of diagnosed WD is~30 per million population, but this is probably an inaccurate estimate as a recent genetic study reported the frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles to be 1/7026 [9].…”