A systematic review of inherited retinal dystrophies in Pakistan: Updates from 1999 to April 2023

AbstractBackground Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023. Methods Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines. Results A total of 359 sequence variants in 89 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 90% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (43%), followed by frameshift (26%), nonsense (18.7%), splice site (12%) and synonymous change (< 1%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77% vs. 23%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber’s congenital amaurosis (LCA). Altogether, mutations inPDE6Agene was the leading cause of IRDs in Pakistani families followed by mutations inTULP1gene. Conclusion In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of pathogenic variants in homozygous state.