Pathogenic variation underlying rare diseases in an Arab Population: implications for screening programs

Abstract

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

Methods: Using the ACMG/AMP guidelines, we curated pathogenic and likely pathogenic variants in 1,333 Arab Emirati families (346 internal cohort and 987 from the literature). We also analyzed coding pathogenic variants in 1,194 Emirati exomes, calculated allele frequencies, and estimated carrier rates for the associated recessive conditions.

Results: Among the 1,333 families, 701 out of 855 variants met the ACMG/AMP criteria for pathogenicity, with 52% and 30% being absent from the gnomAD and ClinVar databases, respectively. Independently, we determined the frequency of coding pathogenic variants in 1,194 Emirati exomes as well as cumulative gene-disease carrier rates. The <italic>CYP21A2</italic> gene showed the highest carrier rate (10.6%) followed by <italic>HBB</italic> (9.6%), <italic>MEFV</italic> (5.9%) and <italic>ABCA4</italic> (4.3%). Using a provisional gene list for carrier screening, based on our analysis, we estimate the rate of at-risk couples (4–21%) which varies across different screening gene lists recommended in other populations.

Conclusion: 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.