Clinical Exome Sequencing for Inherited Retinal Disorders at a Tertiary Care Center

Abstract Purpose: Inherited retinal disorders are clinically, and genetically heterogeneous diseases characterized by progressive deterioration of vision. This study aimed at assessing the diagnostic yield of exome sequencing (ES) for an unselected cohort of individuals with hereditary retinal disorders.Design: It is a retrospective study of 357 unrelated affected individuals, diagnosed with retinal disorders who underwent clinical ES.Methods: Variants from ES, were filtered, prioritized, and classified using the ACMG recommendations. Results: Clinical diagnosis of the individuals included -rod-cone dystrophy (59%), macular dystrophy (20%), cone-rod dystrophy (9%), cone dystrophy (4%) and other phenotypes (8%). Majority of the cases (74%) were singletons and 6% were trios. A confirmed molecular diagnosis was obtained in 23% of cases. In 6% of cases, two pathogenic variants were identified with phase unknown, bringing the potential molecular diagnostic rate to ~29%. Including the variants of uncertain significance (VUS), potentially significant findings were reported in 63% of cases. Among cases with a confirmed molecular diagnosis, variants in EYS, ABCA4, USH2A, KIZ, CERKL, DHDDS, PROM1, NR2E3, CNGB1, ABCC6, PRPH2, RHO, PRPF31, PRPF8, SNRNP200, RP1, CHM, RPGR were identified in more than one affected individual. Conclusions: Our results support the utility of clinical ES in the diagnosis of genetically heterogeneous retinal disorders.