Gaucher disease is an autosomal recessively inherited disorder caused by mutations of the GBA gene. At present, more than 200 mutations have been established ( racheli/genedis/gaucher/gaucher.html).

The gene, which has been mapped to chromosome 1q21, is comprised of 11 exons ( 7 kb) and encoded by a cDNA strand of about 2.5 kb. There are two upstream start codons (ATG) that are both utilized in translation. A highly homologous pseudogene ( 5 kb) showing 96% exonic sequence similarity is located 16 kb downstream. The GBA gene mutations are numbered according to their position in the cDNA relative to the upstream ATG codon (where the A is designated 1), or identified on the basis of the amino acid position in the protein sequence. The abnormal alleles include exonic missense and nonsense mutations, splice junction mutations, deletions or insertions of one or more nucleotides, and complex alleles resulting from gene conversion or recombination. Four mutant alleles (N370S, L444P, 84GG, IVS2+1) account for the majority of disease-causing alleles. Screening studies involving Ashkenazi Jews revealed that the two most common mutations, N370S and 84GG, have a frequency of 0.032 and 0.00217, respectively, and account for approximately 77% and 13%, respectively, of the mutant alleles found in this population.

Genotype–phenotype correlations are imperfect, and the wide variability in clinical presentations among Gaucher disease patients represents a major confounding issue in genetic counselling. The common mutations have been associated with various clinical subtypes, although the presence of at least one N370S allele appears to preclude the development of neuropathic involvement.