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.