A Foundational Exome Resource for Jordan: Dual Ancestry Admixture and Population-Specific Variants to Improve Clinical Variant Interpretation

Currently, the genetic architecture of Middle Eastern populations is underrepresented in global genomic databases. This gap increases the rate of Variants of Uncertain Significance (VUSs) and clinical misinterpretations of genomic data especially in Middle Eastern populations. Whole exome sequencing was conducted on 90 healthy individuals from Jordan and the data were analysed using Principal Component Analysis (PCA) and multi-computational filtering. PCA revealed a double ancestry (EUR-AFR) admixture rather than a triple admixture (EUR-AFR-AMR). More than 3,500 populations-specific variants (PSVs) were identified, of which 72% were singletons. Additionally, 19 variants were significantly enriched compared to the maximum allele frequencies in public global databases (Fisher's exact test with Benjamini-Hochberg false discovery rate correction, p-value < 0.05). Consequently, the results suggest the reclassification of variants of Uncertain Significance (VUS) which reside in the ECE2 gene to likely benign and the variants of Conflicting Classification of Pathogenicity in the genes IL1RN and THPO to benign based on the significant allele frequency (AF=0.0389, p-value < 0.05). Furthermore, a pathogenic ClinVar variant was identified in a healthy individual, warranting careful interpretation. The findings underscore the importance of identifying PSVs in order to minimize or even prevent clinical misdiagnosis and highlight the unique genetic signature in Jordan. The study serves as a foundational resource for precision medicine in the region.