Carrier frequency of the R778L, A874V, and N1270S mutations in the ATP7B gene in a Korean population

To the Editor: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene (1). Although diagnosis of WD usually depends on biochemical findings, the presence of Kayser–Fleischer rings, and/or increased hepatic copper concentration, there is no worldwide consensus on a definitive diagnostic tool (2, 3). The worldwide prevalence of WD is approximately on the order of 30 per 1 million, with a carrier frequency of 1 in 90 (4). WD is thought to be one of the most common autosomal recessive disorders in Koreans. There is even a report on a Korean family with WD in two consecutive generations (5). However, the exact incidence of WD in the Korean population has not yet been determined. In order to estimate the incidence of WD in the Korean population, we investigated the carrier frequencies of the three most common mutations associated with WD in a Korean population. These mutations include c.2333G.T (p.R778L), c.2621C.T (p.A874V), and c.3809A.G (p.N1270S) (6). We recruited 500 healthy Korean subjects from the Health Promotion Center at Samsung Medical Center. This study was approved by the institutional review board. We screened the subjects for the three ATP7B gene mutations using PCR (polymerase chain reaction)–restriction fragment mass polymorphism and confirmed the mutations using PCR sequencing (Fig. 1) (7). We computed the allele frequency and heterozygosity for each mutant site using SAS/GENETICS software (Cary, NC). We found 10 individuals (2%) who were heterozygous for one of the three ATP7B gene mutations: 6 subjects had the p.R778L mutation, 2 had the p.A874V mutation, and 2 had the p.N1270S mutation (Table 1). The estimated allele frequencies were 0.006 (95% confidence interval, CI, 0.00599–0.00601) for p.R778L, 0.002 (95% CI, 0.001998–0.002002) for p.A874V, and 0.002 (95% CI, 0.001998–0.002002) for p.N1270S. Thus, the combined carrier frequency of these three mutations in the Korean population was 1:50 (2%). Given that the three mutations that were investigated represent 54.2% of the genetic variation in Korean WD patients (8), we presume that the carrier frequency of WD is approximately 1 in 27. The prevalence of WD is approximately 1 in 3000. Considering that the carrier frequency of WD in the US Caucasian population, as extrapolated from a mutation-based approach, is 1 in 117 and WD prevalence is 1 in 54,718, our data suggest that WD carriers are more prevalent in Korea (9). However, the true incidence of the three most common mutations in affected patients is slightly lower than 54.2% because there may be more ATP7B mutations that have not been found yet. Mutation analysis