A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield

Abstract Purpose Whole-exome sequencing (WES) can help identify known and novel pathogenic molecular aberrations. Here, we examined the diagnostic yield of WES in population from consanguineous unions. Methods We preformed retrospective review of multicenter WES results of an unselected cohort of patients with a wide range of phenotypes. Clinical data and WES reports of 454 patients from 5 centers across Saudi Arabia were analyzed. Testing was performed in accredited commercial laboratories, and all the WES laboratory reports were reviewed again using additional clinical information available to the treating physicians. Results Among the 454 probands, we identified highly likely disease-causing variants in 222, thereby achieving a 49% molecular diagnostic yield. The diagnostic yield was 53% in consanguineous unions and 39% in non-consanguineous unions. About 66% of the identified variants in consanguineous families were homozygous, with an autosomal recessive mode of inheritance. Additional clinical data reclassified 11 positive reported results into 4 inconclusive and 7 negative results, and 22 inconclusive results into 17 positive and 5 negative results. Conclusions The diagnostic yield from WES in our unselected cohort is similar to other studies from the same region, which is a higher yield compared to other international regions largely because of the high rate of consanguinity and partly due to simplified variant interpretation and classification in consanguineous unions.