Three Gaucher-Disease-Producing Mutations in a Patient with Gaucher Disease: Mechanism and Diagnostic Implications

Abstract

As Gaucher disease is an autosomal recessive disorder, most patients are either homozygotes or compound heterozygotes for glucocerebrosidase mutations. We have encountered a patient with three mutations, two c.1226A→G (1226G, N370S) and one c.1448 T→C (1448C, L444P). This was shown to be due to a gene conversion event in which the sequence of the glucocerebrosidase pseudogene that includes the 1448C mutation had been imposed on a glucocerebrosidase gene that already had the 1226G mutation. The patient had relatively mild disease which had been discovered after an attack of infectious mononucleosis, a relationship that has been observed previously. If it had not been recognized that this patient had the 1226G/1226G,1448C genotype, prenatal testing might have falsely identified a 1226G,1448C/wt (wild type) fetus as having Gaucher disease.

The clinical management of type 2 Gaucher disease

“…Patients heterozygous or homozygous for this mutation do not manifest Type 2 GD. There has, however, been at least one report where Asn370Ser (Asn409Ser) was found on the same allele in cis with another GBA1 mutation, which can further confuse the picture [16]. In contrast, the mutation Leu444Pro (Leu483Pro) is frequently encountered in Type 2 GD, although it is rare to identify patients who are homozygous.…”

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

“…In 2000, Beutler and colleagues first reported an affected GD1 patient with three mutations, the c.1226A>G(p.N370S) missense mutation on one allele and the c.1226A> G(p.N370S) and c.1448T>C(p.L444P) missense mutations on the other (Beutler et al 2000). They recognized the implications for a false-positive prenatal diagnosis for such patients if the fetus had inherited the c.1226A>G(p.N370S)–c.1448C>T(p.L444P) allele and was diagnosed as affected, but was actually a GD heterozygote.…”

Alleles with more than one mutation can complicate genotype/phenotype studies in Mendelian disorders: Lessons from Gaucher disease

“…Remarkably, Beutler et al described a patient with genotype N370S/ N370S who also carried mutation L444P [19]. Additionally, Filcamo et al reported a patient, with GD2 and genotype G202R/G202R (p.G241Rp./G241R), who also carried M361I (M400I) [8].…”