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Gaucher disease: when molecular testing and clinical presentation disagree ‐the novel c.1226A>G(p.N370S)‐‐RecNcil allele
Author(s) -
Balwani Manisha,
Grace Marie E.,
Desnick Robert J.
Publication year - 2011
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-011-9307-7
Subject(s) - allele , proband , genetics , genotype , pseudogene , compound heterozygosity , glucocerebrosidase , biology , hepatosplenomegaly , allele frequency , mutation , medicine , disease , gene , genome
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.