Deciphering the Genetic and Epidemiological Landscape of Inherited Retinal Diseases (IRDs) in a Cohort of Eastern Iranian Patients

Abstract

Inherited retinal diseases (IRDs) may have significant diagnostic challenges due to their genetic complexity and diverse inheritance patterns. Advanced genotyping tools like exome sequencing (ES) offer promising opportunities for identifying causative variants and improving disease management. This retrospective study was aimed to present prevalent pathogenic and novel variants in patients diagnosed with IRDs using ES. We investigated 154 patients diagnosed clinically with IRDs, of which non-syndromic IRDs were more prevalent than syndromic form (~56% vs. ~44%). Out of 154 unrelated patients, 133 (~86%) were genetically resolved, where retinitis pigmentosa was the most common subtype (26% of all resolved patients). Fifty-three previously known and also 56 novel variants across known IRD genes were identified. Autosomal recessive inheritance predominated in both resolved forms (112/133, 84.21%), with 46 novel variants. This could be due to high rate of consanguinity in the studied families (114/133 patients, 85.71%). The two previously reported ancestral founder pathogenic variants in TMEM67 (c.725A > G) and BBS2 (c.471G > A) genes, as well as the most common variant in AIPL1 gene (c.834G > A), were also prevalent in our patients. Interestingly, identical novel compound heterozygote of the CEP290 gene (c.3167C > A and c.7024C > T) were identified in two unrelated cases. This retrospective study was the first attempt in terms of sample size and diversity to add more to our current knowledge of the genetic makeup of IRDs in a population from the East of Iran. Our findings can facilitate genetic counselling and subtype classification of IRDs, especially in challenging cases.