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

Abstract

Population studies point to regional and ethnicity‐specific differences in genetic predisposition for some lysosomal storage disorders (LSDs). The aim of the study was to determine the prevalence of the three treatable forms of lysosomal storage disorders (Gaucher disease [GD], Pompe disease [PD], and Fabry disease [FD]) in a cohort of mostly urban‐dwelling individuals of African ancestry, a previously unknown genetic landscape for LSDs. Large‐scale selective multistep biochemical and genetic screening was performed in patients seeking healthcare for various health concerns. Fluorimetric enzyme assays for GD, PD, and FD were performed on dried blood spots. Targeted gene sequencing was performed on samples that showed significantly lower enzyme activities (<10% of control mean) after two tiers of enzymatic screening. A total of 5287 unique samples representing a cross section of patients who visited Howard University Hospital and College of Medicine from 2015 to 2017 were included in the study. Study samples were obtained from a population where ~90% reported as African‐American, ~5% Hispanic, and <5% Caucasian or other. Regarding GD, three subjects had either 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. Regarding FD, two subjects had pathogenic GLA mutations, and four had single nucleotide polymorphisms in the 5'UTR, previously implicated in modulating gene expression. The findings highlight a higher incidence of abnormal enzyme levels and pathogenic mutations in the target population reflecting ancestry‐based specific genotype and phenotype variations.

The Opioid Epidemic: a Crisis Disproportionately Impacting Black Americans and Urban Communities

“…Treatment approaches that are one-size-fits-all based on regimen developed with White research participants and few to no African Americans must be carefully vetted, as discussed by our group in Abijo et al, Gondré-Lewis et al, and Limgala et al [27,51,52]. Vulnerability to cancers, systemic, and psychiatric disorders can vary by ethnicity, but opioid addiction can as well [53,54].…”

Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations

“…In the United States of America, the inclusion of Pompe disease in NBS was recommended in 2015, and currently more than 20 states have started the necessary implementation steps ( 15 ). The incidence of Pompe disease is historically reported as ~1:40,000 live births Western countries ( 16 ); however, this epidemiology has been calculated mainly based on European populations, with blind studies showing a higher incidence in other populations including people of African ancestry ( 17 ). Moreover, after implementation of universal screening through NBS there have been many reports of an incidence up to 4x higher than expected [as summarized by Davids et al ( 18 )], pointing to a substantial amount of historically missed diagnoses.…”

Screening for potential undiagnosed Gaucher disease patients: Utilisation of the Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS) in conjunction with electronic health record data, tissue specimens, and small nucleotide polymorphism (SNP) genotype data available in Finnish biobanks

“…The actual prevalence of GD in Finland is not known, and it has been hypothesized that GD is possibly underdiagnosed in this country. In accordance with worldwide attempts to identify potential undiagnosed patients [ [11] , [12] , [13] , [14] ], we have set up a retrospective screening approach in the unique Finnish biobank landscape that allows the screening of considerably large populations with data and samples readily available. The overall aim of the current and the previous study [ 15 ] was to utilise the GED-C PSS of GD type 1/3 [ 16 ] and data and samples available in Finnish biobanks in the screening of GD.…”

“…To increase the diagnostic rate in GD, high-risk subjects, e.g., patients diagnosed with splenomegaly, thrombocytopenia, or plasma cell dyscrasias, have been screened by utilising standard enzyme, biomarker, and genetic diagnostic tools [ 11 , 12 ]. In addition, larger cohorts comprising of up to ca 5,300 individuals, have been screened by utilising left-over blood samples collected in routine care or available laboratory data a priori followed by the testing of separately collected specimens [ 13 , 14 ]. The prevalence of GD in the tested high-risk and hospital populations was 0–3.3% and 0–0.019%, respectively [ [11] , [12] , [13] , [14] ].…”

“…In addition, larger cohorts comprising of up to ca 5,300 individuals, have been screened by utilising left-over blood samples collected in routine care or available laboratory data a priori followed by the testing of separately collected specimens [ 13 , 14 ]. The prevalence of GD in the tested high-risk and hospital populations was 0–3.3% and 0–0.019%, respectively [ [11] , [12] , [13] , [14] ].…”