The American College of Medical Genetics and Genomics (ACMG) recommends Tier-3 reproductive carrier screening for 97 genes associated with autosomal recessive conditions (AR genes). Gene selection for screening is based on a gene carrier frequency (GCF) of ≥1/200 in the Genome Aggregation Database (gnomAD)v2 populations and disease severity. The utility of ACMG Tier-3 in the Middle Eastern population is unclear as this ancestral group was not represented in the gnomADv2. We utilized genome data from 14,392 individuals in the Qatar Genome Project to estimate the carrier frequency of autosomal recessive conditions in the Middle Eastern population. The frequency of 136,624 Pathogenic/Likely Pathogenic variants in 2,987 AR genes from ClinVar was analyzed to estimate the GCF in the Qatari cohort. Genes with GCF≥1/200 were curated by an expert panel for the severity of corresponding conditions. We identified 69 genes with GCF≥1/200 associated with moderate to profound clinical presentations, 53 of which were unique to the Middle Eastern population. Common variants were observed with high frequency for individual genes such as IL2RA that suggested the presence of founder effects not described previously. Simulation studies predicted that inclusion of the ancestry-specific genes increased the chance of detecting at-risk couples from 3.85% to 8.15% in the Middle Eastern population. This study highlights the limitations of relying on global datasets to accurately identify the candidate genes for carrier screening in different populations. Our findings provide a framework for targeted, population-specific carrier screening programs in regions not represented in the large genome datasets.
Nkrumah et al. (Fri,) studied this question.