Selective screening for lysosomal storage disorders in a large cohort of minorities of African descent shows high prevalence rates and novel variants

JIMD Rep 2021 Jan 27;59(1):60-68. doi: 10.1002/jmd2.12201. eCollection 2021 May.

PMID: 33977031

Renuka Pudi Limgala , Vyacheslav Furtak , Margarita M Ivanova

Highlights: The study's goal was to determine the prevalence of the three treatable types of lysosomal storage disorders (Gaucher disease [GD], Pompe disease [PD], and Fabry disease [FD]) in a cohort of primarily urban-dwelling Africans, a previously unexplored genetic environment for LSDs.

Abstract

Objective: Regional and ethnic variations in genetic predisposition for certain lysosomal storage disorders (LSDs) have been discovered in population studies. The study's goal was to determine the prevalence of the three treatable types of lysosomal storage disorders (Gaucher disease [GD], Pompe disease [PD], and Fabry disease [FD]) in a cohort of primarily urban-dwelling Africans, a previously unexplored genetic environment for LSDs.

Methods: Patients seeking treatment for a variety of conditions were subjected to a large-scale, multistep biochemical and genetic screening. On dried blood spots, fluorimetric enzyme assays for GD, PD, and FD were performed. After two tiers of enzymatic screening, samples with considerably reduced enzyme activity (< %10 of control mean) were subjected to targeted gene sequencing. The study includes 5287 distinct samples from a cross section of patients who attended Howard University Hospital and College of Medicine between 2015 and 2017. The study included samples from a community in which ~90% of people identified as African-American, ~5% as Hispanic, and ~5% as Caucasian or other.

Results: Regarding GD, three of the individuals had homozygous or heterozygous mutations in the GBA gene. As to PD, eight subjects were either homozygous or compound heterozygous for GAA mutations, including three novel mutations: (a) c.472 A > G; p.T158A, (b) c.503G > T; p.R168L, (c) c.1985del. Two of the subjects had pathogenic GLA mutations, and four had single nucleotide polymorphisms in the 5'UTR, which have previously been linked to gene expression modulation.

Conclusion: The data show that the target group had a greater incidence of abnormal enzyme levels and pathogenic mutations, owing to ancestry-based genotype and phenotype variations.

Keywords: African‐Americans, Fabry disease, Gaucher disease, Pompe disease, large‐scale screening, lysosomal storage disorders