title: Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele.
abstract: 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.
authors: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, Fifth Avenue at 100th Street, Box 1498, New York, NY 10029, USA.
authors: Manisha
authors: M
authors: Balwani
authors: Marie E
authors: ME
authors: Grace
authors: Robert J
authors: RJ
authors: Desnick
mesh_terms: D000328:Adult; D000483:Alleles; D003937:Diagnosis, Differential; D005260:Female; D005776:Gaucher Disease / Q000175:diagnosis* / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D025202:Molecular Diagnostic Techniques; D010808:Physical Examination / Q000379:methods; D020641:Polymorphism, Single Nucleotide
chemical_list: D005962:Glucosylceramidase