A comprehensive genetic landscape of inherited retinal diseases in a large Pakistani cohort

Inherited retinal diseases (IRDs) are a group of rare Mendelian disorders that often result in progressive vision loss and potentially to complete blindness at the end stage. In this study, we investigated a large cohort of patients with IRDs from Pakistan, the world's fifth most populous country, which is also characterized by distinctive demographic features, such as a high prevalence of consanguinity, endogamy, and a wide variety of ethnic groups. Specifically, we examined a total of 213 unrelated families (722 affected individuals) from three very large geographical regions. We achieved precise molecular diagnosis in 171 pedigrees (80.3%) and detected causative variants in 60 different IRD-associated genes, revealing a mutational landscape that differed substantially from previous data from other European or Asian populations, heavily shaped by endogamy and rare or recurrent founder mutational events. To our knowledge, this work represents the largest genetic study on IRDs within the Pakistani population.