Molecular diagnosis of Wilson disease

Wilson disease (WD) is caused by mutations in the ATP7B gene. The diagnosis is based on clinical and biochemical criteria but these are increasingly r ecognized to have low sensitivity. Genetic diagnosis is considered impracti cal due to the large coding region of the ATP7B gene and extreme diversity of mutations. We assessed the feasibility and utility of genetic diagnosis in WD. The coding region of the ATP7B gene was scanned by single-stranded c onformation polymorphism (SSCP) analysis in 6 cases in whom the diagnosis o f WD was uncertain. In addition, we attempted molecular diagnosis in 26 WD patients of similar ethnicity but variable disease manifestations. In 6 ind ividuals in whom the biochemical/clinical diagnosis was uncertain, DNA anal yses were useful for assigning their status with respect to WD. Molecular d iagnosis identified presymptomatic individuals in families affected by WD a nd assigned heterozygote carrier or wild-type status to individuals previou sly diagnosed as affected. In 26 WD patients, 92% of disease alleles were i dentified. The most common mutations were H1069Q, L936X, and 2532deLeA repr esenting 48, 10, and 8% of disease alleles, respectively. Three novel mutat ions were identified: Q898R, 3061(-1)g --> a, and 3972insC. Genetic diagnos is is feasible for WD. Greater application of molecular diagnosis should en able an appreciation of the full spectrum of WD phenotype that is not possi ble with currently available diagnostic criteria. (C) 2001 Academic Press.