1. ¹Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
2. ²Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China
3. ³Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
4. ⁴Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
5. ⁵Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
6. ⁶Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
7. ⁷Department of Medicine, Princess Margaret Hospital, Hong Kong, China
8. ⁸Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
9. ⁹Department of Pathology, Tuen Mun Hospital, Hong Kong, China
10. ¹⁰Department of Pediatrics, Tuen Mun Hospital, Hong Kong, China
11. ¹¹Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China
12. ¹²Department of Pediatrics and Adolescent Medicine, Caritas Medical Center, Hong Kong, China
13. ¹³Department of Medicine and Geriatrics, Caritas Medical Centre, Sham Shui Po, Hong Kong, China
14. ¹⁴Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China
15. ¹⁵Department of Adult Intensive Care Unit, Queen Mary Hospital, Hong Kong, China
16. ¹⁶Department of Pathology, Princess Margaret Hospital, Hong Kong, China

Correspondence: Ching-Wan Lam, Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. E-mail: ching-wanlam@cuhk.edu.hk

Chloe M Mak and Ching-Wan Lam contributed equally to this paper.

Received 12 September 2007; Accepted 22 October 2007; Published online 22 November 2007.

Abstract

Wilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.