Carrier frequency of Wilson’s disease in the Korean population: a DNA-based approach

Abstract

Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B gene mutation. The frequency of WD is about 1 in 30 000 worldwide. In the present study, we screened 14 835 dried blood spots (DBSs) from asymptomatic Korean neonates and retrospectively reviewed massively parallel sequencing of 1090 control individuals to estimate carrier frequency. TaqMan real-time PCR assays were conducted to detect six mutations that account for 58.3% of mutations in Korean WD patients: c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val), c.3086C>T (p.Thr1029Ile), c.3247C>T (p.Leu1083Phe), c.3556G>A (p.Gly1186Ser) and c.3809A>G (p.Asn1270Ser). We also retrospectively reviewed data from 1090 individuals with various indications other than WD for whom whole-exome or panel sequencing data were available. Mutant allele frequency based on the six most common mutations was 0.0067 among the total of 14 835 DBSs screened. Given that these six mutations account for 58.3% of mutations in Korean WD patients, the corrected mutant allele frequency is 0.0115 (95% confidence interval (CI): 0.0103-0.0128). Corresponding incidence (q) and carrier frequency (2pq) were estimated to be 1:7561 and 1:44, respectively. In retrospective data analysis of 1090 control individuals, allele frequency of pathogenic or likely pathogenic variants was 0.0096 (95% CI: 0.0063-0.0146). Corresponding carrier frequency was estimated to be 1:53. Estimated allele and carrier frequencies based on DNA screening were relatively higher than those reported previously based on clinical ascertainment.

High genetic carrier frequency of Wilson’s disease in France: discrepancies with clinical prevalence

“…When based on the VUS parameter, the heterozygous prevalence of ATP7B (1/19) was found to be similar than that described in the British population (1/18) [8]. Among the five VUS described during our study (p.Val536Ala, p.Glu541Lys, p.Met665Ile, p.Val1297Ile and p.Thr1434Met), three (p.Val536Ala, p.Glu541Lys, p.Met665Ile) had been reported in Coffey’s publication as being benign.…”

“…Our NGS approach was similar to that used by Coffey et al [7] and Jang et al [8]. We only included variants with probably pathogenic or pathogenic deleterious effects.…”

“…Firstly, account needs to be taken of the discrepancies between the clinical and genetic frequencies seen both in France [9] and worldwide [7, 8], for different reasons. The diagnosis is certainly underestimated, or the pathology may be misdiagnosed.…”

“…Subsequent epidemiological studies have suggested a lower clinical prevalence of WD in European countries with a low degree of consanguinity, estimated at between 12 and 20 per one million [6]. Nevertheless, genetic prevalence appears to be higher than clinical prevalence, as shown by two recent British and Korean studies which produced heterozygous carrier frequencies of 1/25 and 1/53, respectively [7, 8]. …”

The Prevalence of Wilson’s Disease: An Update

“…Four studies from South Korea analyzed the frequency of the 3, 4, 6, or 7 most common mutations in South Korea in samples from 500, 476, 14,835, and 3,057 individuals, respectively. The corresponding genetic prevalence estimates were 1:3,000, 1:30,800, 1:7,500, and 1:27,000, respectively . These results have been taken to suggest a higher prevalence in South Korea than in the rest of the world, but selection biases may have hampered this conclusion.…”