Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele

We report a 31 year old woman who had prenatal carrier screening for Ashkenazi Jewish (AJ) genetic diseases and was found to have two acid ß-glucosidase (GBA) mutations, c.1226A>G(p.N370S) and c.1448T>C(p.L444P), consistent with the diagnosis of Type 1 Gaucher disease (GD1). This genotype typically manifests in late-adolescence with hepatosplenomegaly and early-onset bone involvement. The Proband had a normal physical examination, no organomegaly, and normal blood counts, skeletal survey, and bone density. Leukocyte acid ß-glucosidase and plasma chitotriosidase activities were normal. To investigate these unexpected results, her GBA alleles were RT-PCR amplified and sequenced. Five RT-PCR clones were negative for both mutations, while five clones had the c.1226A>G(p.N370S) and c.1448T>C(p.L444P) mutations, along with c.1483G>C(p.A456P), and c.1497G>C(p.V460V) mutations, the latter three lesions composing the rare GBA pseudogene-derived RecNcil allele. Genetic testing misdiagnosed the asymptomatic Proband as affected with Type 1 Gaucher disease; however, molecular studies revealed a novel allele with the two common GBA mutations on the RecNcil background. This allele presumably arose by crossing-over between a c.1226A>G allele and the pseudogene, gene conversion, or a new c.1226A>G mutation on the RecNcil background. This novel complex allele highlights a limitation of carrier screening for GD.