High prevalence of the H1069Q mutation in East German patients with Wilson disease:: rapid detection of mutations by limited sequencing and phenotype-genotype analysis

Background/Aims: Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. Methods: Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. Results: Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3 +/- 7.2 years) than in H1069Q compound heterozygotes (14.6 +/- 5.8, P < 0.001) or H1069Q negatives (10 +/- 4.4, P < 0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P < 0.001) and Kayser-Fleischer rings (82 vs. 51%, P < 0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or Cu-64-assay results. Conclusions: In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.