Diagnostic whole exome sequencing in presumably autosomal recessively inherited retinal dystrophies in an Iranian population

Abstract

Purpose : Genetic testing in inherited retinal dystrophies (IRD) allows for confirmation of diagnoses and accurate identification of inheritance pattern, thereby improving genetic counselling and opening up options for potential (gene) therapy for affected individuals and their families. IRDs can show various inheritance patterns, e.g. autosomal dominant, autosomal-recessive, and X-linked inheritance. In this study, we aimed to uncover the genetic causes of presumably autosomal recessively inherited IRDs in a cohort of patients from Iranian descent.

Methods : IRD patients were recruited by ophthalmologists of the Tehran University of Medical Sciences. Whole exome sequencing (WES) was performed using a gene panel including ~500 genes involved in inherited eye disorders. Variants were classified according the ACMG guidelines using Alamut Visual, the CADD scoring website and the online Franklin tool. Unsolved cases are currently being taken forward for CNV analyses and analyses of relevant (homozygous) ariants outside of the gene panel.

Results : 111 patients (58 females, 53 males) with inherited retinal dystrophies [VV1] were recruited and successfully underwent WES. Mean age at recruitment was 37.2 years old (SD11.2 yrs; age range 15-68). The majority of the cohort originated from a consanguineous background, mostly due to first cousin marriages. [VV2] In 59% of the cases, we found a causative variant; in another 31% of the cases, we found a potentially causative variant.[MMS3] In 86% of the IRD cases, the inheritance pattern was autosomal recessive (homozygous variant n=91, compound heterozygous variants n =5). The most frequently (≥5%) involved genes were CERKL (10%), CRB1 (9%), EYS (7%), ABCA4 (7%), RPE65 (6%), RP1 (5%), and MERTK (5%) .

Conclusions : Using WES with a filter for known IRD genes as a first-tier genetic test in this consanguineous IRD Iranian cohort, we were able to identify a (potential) causative (homozygous) variant in almost 90% of the cases. Expanding the WES analyses with CNV analysis and filtering outside of the panel will probably even increase the diagnostic yield.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.