Whole‐Exome Sequencing analyses of Saudi Stroke. Stroke Whole Exome

Introduction: Ischemic stroke (IS) represents a significant societal burden across the globe. Rare high penetrant monogenic variants and less pathogenic common single nucleotide polymorphisms (SNPs) have been described with risk of disease. Consanguineous populations from Saudi Arabia offer a greater opportunity to detect rare high penetrant mutations enriched in tribal populations. Methods: We performed WES on 387 IS subjects from Saudi Arabian hospital networks with > 20,230 controls from the Saudi Human Genome Project. Results: We prioritized screening of variants from 177 a priori loci derived from knowledge-driven curation of monogenic and genome-wide association studies of stroke. We observed 8 genes with a significant association under autosomal dominant and recessive modelling which included IVD, KCNE2, KCNK3, FOXF2, HBB, MGAT2, FOXC1 and CD59. Stroke subjects with modified Rankin Scale (mRSs) above 3 were found to carry greater cumulative genetic risk from rare variants in stroke genes (standardized PRS mean>0), compared to the population average (standardized PRS mean=0). However. patients with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes (OR (95%CI) = 1.79 (1.29 – 2.49), p=0.0005), with the means of standardized PRS at or lower than 0. Conclusion: Determining the potential mRS cutoffs to use for clinical significance within a highly consanguineous population like that in Saudi Arabia may yield translational value, such as risk stratification, especially with the additional of common and rare variants to evolving PRS from ongoing stroke genome-wide association studies.