Gaucher Disease: Gene Frequencies and Genotype/Phenotype Correlations

Abstract

Gaucher disease is the most prevalent lysosomal storage disease and has its highest incidence in the Ashkenazi Jewish population. Over 100 mutant alleles have been identified in affected patients, but four alleles, termed N370S, L444P, 84GG, and IVS2, have significant frequencies in this population. In affected patients, genotype data show that the presence of a single N370S allele is diagnostic of the type 1 or nonneuronopathic variant, whereas the L444P/L444P genotype is highly associated with neuronopathic variants in the Caucasian population. Large screening studies also indicate a significant underestimation (approximately two-fold) of the prevalence of the N370S/N370S genotype in the affected Ashkenazi Jewish patient population. These results indicate that the N370S/N370S genotype provides a necessary but not sufficient condition for the development of the Gaucher disease phenotype. The genotype/phenotype correlations and gene frequencies have significant impact on genetic counseling of at-risk couples and the future need for therapy of affected patients.