Uncovering the genetic architecture of inherited retinal disease in a consanguineous Iranian cohort

Abstract

Abstract An integrated approach combining whole exome sequencing (WES) and autozygosity mapping was used to molecularly diagnose inherited retinal disease (IRD) in 192 unrelated Iranian families, 76.1% of which originate from a consanguineous background. Data analysis was performed using an in-house pipeline to detect single-nucleotide variants (SNVs), small insertions and deletions, copy number variants (CNVs) and runs of homozygosity (ROHs). Using this approach, we obtained a molecular diagnosis for 72.9% of the cohort. In total, 209 variants were identified in 78 IRD-associated genes. The majority occurred only once (81.8%) and 52.9% were novel. Variants in ROHs were found in 82.8% of patients from consanguineous backgrounds. The importance of structural variation (SV) was demonstrated, with CNVs identified in 5.3%, including several novel CNVs. Multilocus genomic variation was observed in two families. This integrated study using WES and in-depth variant assessment significantly expanded the molecular spectrum of IRD in Iran, an understudied population.