Spectrum of Mutations in the ATP7B Gene in Russian Patients with Wilson's Disease

Wilson's disease (WD) is an autosomal recessive disease caused by an excessive accumulation of copper. The molecular genetic etiology of the disease is due to impairment of the ATP7B gene encoding copper-transporting ATPase. The spectrum and frequencies of mutations in the ATP7B gene are reported in the present study. The analysis was performed via allele-specific ligation for the search for frequent mutations, via massive parallel sequencing for the search for rare nucleotide substitutions, and via Multiplex Ligation-dependent Probe Amplification (MLPA) for the analysis of the copy number of all exons in the ATP7B gene. This study summarizes the findings from 431 DNA samples of patients with a preliminary diagnosis of Wilson's disease analyzed for pathogenic ATP7B variants. DNA samples of 1000 unexamined individuals from different regions of the Russian Federation were used to estimate population frequencies. The spectrum of mutations in the ATP7B gene was determined in patients from Russia. A total of 66 different variants of the nucleotide sequence in the ATP7B gene were revealed, including 42 previously described pathogenic variants and 24 primarily identified ones. The most frequent pathogenic ATP7B variant in the Russian population of patients with Wilson's disease was missense mutation c.3207C>A present in 50% of mutant alleles. Pathogenic variants c.2403insC, c.3204delC, c.3036insC, and c.3190G>A were also found to be more prevalent. The expected number of patients with Wilson's disease in the studied sample was 208 of 431 individuals. The cause of the disease was established in 78% of patients with hepatolenticular degeneration. The carrier frequency of Wilson's disease was found to be 1 per 50 individuals from Russia (confidence interval from 1 : 42 to 1 : 63). The calculated frequency of the disease is 1 per 10 000 individuals from Russia (confidence interval from 1 : 8333 to 1 : 12 500).