Genetic diagnosis of Gaucher's disease.

The inherited disorder Gaucher's disease can be caused by various mutations in the glucocerebrosidase gene. Some mutations may be associated with greater severity, and there is a need for methods of gene analysis that would facilitate screening and diagnosis. We have studied the molecular basis of Gaucher's disease in twelve unrelated patients of diverse ethnic origin by means of the amplification refractory mutation system (ARMS). Primers for the polymerase chain reaction were designed to discriminate between mutant and wild-type alleles of glucocerebrosidase and to allow separation from products of the related pseudogene. The nucleotide 1226 mutation (asparagine 370----serine) and 84GG (an insertional frameshift mutation) were found exclusively in five patients of Ashkenazi Jewish descent (7 and 2 of the 10 disease alleles, respectively). Two point mutations, at nucleotides 1448 (leucine 444----proline) and 1504 (arginine 463----cysteine), were found in 4 and 3 alleles, respectively; they were associated with rapidly progressive disease and neurological involvement in non-Jewish patients. The ARMS procedure for direct detection of common mutations in glucocerebrosidase will facilitate genetic counselling and screening programmes for individuals at risk of Gaucher's disease.