Pathogenic variation underlying rare diseases in an Arab population: Implications for screening programs

Genetic variation underlying rare diseases in Arab populations is poorly understood limiting effective carrier screening for recessive disorders, which are prevalent because of high consanguineous rates.

Using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, we curated pathogenic (P) and likely pathogenic (LP) variants in 1333 Arab Emirati families (346 internal cohort and 987 from the literature). We also analyzed P/LP variants in 1194 Emirati exomes, calculated allele frequencies, and estimated carrier rates for the associated recessive conditions.

Among the 1333 families, 1060 had 701 variants meeting the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria for pathogenicity, with 52% and 30% being absent from the Genome Aggregation Database and ClinVar databases, respectively. Independently, we determined the frequency of P/LP variants in 1194 Emirati exomes, as well as cumulative gene-disease carrier rates. The CYP21A2 gene (HGNC:2600) showed the highest carrier rate (10.6%) followed by HBB (HGNC:4827) (9.6%), MEFV (HGNC:6998) (5.9%), and ABCA4 (HGNC:34) (4.3%). Using a provisional gene list for carrier screening, based on our analysis, we estimated an at-risk couples rate of 4% to 21%, which varies across different screening panels recommended in other populations.

Our findings emphasize the necessity of identifying prevalent diseases in underrepresented populations to develop effective and equitable preventive public health measures, including premarital screening programs.