Clinical and family history data on persons affected with Wilson disease (WD) living in Israel between 1958 and 1984 were ascertained from the literature, hospital records and neurological and gastroenterological clinics. From this population of 51 families, representing a diversity of Middle Eastern. North African and European backgrounds, blood samples were collected from affected individuals in 21 families, their parents, sibs and other relatives for quantitative determinations of plasma copper and ceruloplasmin, liver tests and DNA analysis. Although the majority of patients have the hepatic form of the disease, hepatic and neurological cases were found among all ethnic groups. In fact, affected sibs in several inbred families who most likely inherited two copies of the same mutant allele had different symptoms. Gene frequencies were calculated for each of the populations taking into account inbreeding, probability of ascertainment, and estimated incidence. Although many of these communities have gene frequencies which are comparable to worldwide estimates, high prevalence of disease is maintained by consanguineous mating patterns. Probabilities of WND genotypes were calculated for 129 unaffected relatives who had an a priori risk of inheriting at least one WND allele using information from 10 DNA markers closely linked to the WND locus. There was no evidence that multiple loci are responsible for the observed clinical variability in this sample of families. Furthermore, studies of serum copper and ceruloplasmin levels in unaffected relatives suggest that phenotypic variability in WD may be due in part to an interaction of the WND locus with other genetic or non-genetic modifiers such as age.