Gaucher disease in North Macedonia: Unexpected prevalence of the N370S GBA1 allele with attenuated disease expression

Mol Genet Metab Rep. 2022 Jul 8;32:100895. doi: 10.1016/j.ymgmr.2022.100895.

PMID: 35845720

Nevenka Ridova, Sanja Trajkova, Biljana Chonevska

Highlights: This study summarizes the genetic and phenotypic "portraits" of 14 patients with Gaucher Disease (GD) type 1 in the Republic of North Macedonia, 4 of Macedonian and 10 of Albanian origin.

Abstract

Background: Pathologic mutations in the GBA1 gene are responsible for the majority of Gaucher Disease (GD) patients. About 500 identified variants form a diverse mutational spectrum that has been recognized. Phenotypic diversity is a feature of the disease. There are little and conflicting data on the genotype-phenotype correlation.

Objective and results: The genetic and phenotypic "portraits" of 14 GD type 1 patients from the Republic of North Macedonia —4 of Macedonian and 10 of Albanian origin— are summarized in this article. Six distinct genotypes were compounded from the total of 6 variants that were found. The N370S variant, which had an overall prevalence of 60.7%, was present in all genotypes. The double mutant allele D409H;H255Q and the 1263del55 deletion, both of which were common variants, each had a 14.2% prevalence. Two uncommon mutations were found: D399N, a single nucleotide variant with uncertain pathogenicity, and W92*, a pathogenic nonsense mutation. The most prevalent genotypes were N370S/1263del55 and H255Q;D409H/N370S, both of which were present in 4/14 patients. N370S homozygosity was also observed in 3/14 patients. All patients had splenomegaly, which was the most frequent clinical symptom. In 50% of cases, hepatomegaly was evident despite being less common. 9/14 of the patients developed thrombocytopenia, while anemia affected 50% of the patients. In 8 individuals, bone pathology was seen.

Conclusion: High levels of clinical heterogeneity were seen among patients of various genotypes, indicating that the other allele determines the onset and severity of the disease in patients with the N370S mutation. To better characterize the relationship between the genotypic and phenotypic expression in GD, larger patient cohorts, longer follow-up, and multicentric investigations should be carried out.

Keywords: Gaucher disease, Genetic-phenotypic correlations, Macedonian population, Mutations, Phenotypic profile