Identification of novel candidate genes for inherited retinal disorders in consanguineous families from Pakistan and Iran

Abstract

Purpose : Consanguinity provides a unique opportunity to identify novel gene-phenotype correlations. Children of consanguineous parents have an average genomic homozygosity of 253 Mb, which is 10-fold higher than outbred individuals. This feature facilitates the identification of high-impact genomic variants for autosomal recessive disorders. Pakistan and Iran are among the most consanguineous countries in the world, with such marriages accounting for up to 70% and 38.6%, respectively. The purpose of this study was to identify novel candidate genes for Inherited Retinal Disorders (IRDs) by studying consanguineous families.

Methods : This study presents the genetic analysis of 218 large consanguineous families (817 patients) collected from Pakistan and Iran, most of which had more than one affected individual. Retinitis pigmentosa (RP) was the most observed phenotype, followed by Leber congenital amaurosis (LCA) and Stargardt disease. Whole exome sequencing (WES) was performed on affected individuals, and genotyping of potential variants was carried out in all family members (parents and all siblings).

Results : The overall diagnostic yield for known IRD genes was 72% (156 of 218 families). The most frequent mutant causative genes were CRB1, ABCA4, and AIPL1, identified in 15, 11, and 9 families, respectively. In the 62 undiagnosed families, we identified several novel candidate genes, including MOB1A (c.503C>G, p.Ser168Cys), CCDC180 (c.1969_1970del, p.Asn657ArgfsTer10), PLA2G3 (c.601C>T, p.Arg201Ter), ATP8A1 (c.3043C>T, p.Pro1015Ser), and MPHOSPH6 (c.414T>G, p.Tyr138Ter). PLA2G3 and CCDC180 have previously been associated with ciliary dysfunction, which has been shown to cause various ocular diseases. A Ccdc180 -/- mouse model exhibited pronounced ocular phenotypes (IMPC). MOB1A regulates YAP1 activity, which has previously been linked with IRD. Both ATP8A1 and MPHOSPH6 are expressed in the eye, but their roles in visual function are not well understood.

Conclusions : This study demonstrates the power of WES in elucidating the genetic architecture of IRDs in consanguineous families. The identification of novel candidate genes expands our knowledge of the molecular pathways involved in these disorders and paves the way for future therapeutic interventions. Additionally, these findings have the potential to improve molecular diagnosis and genetic counseling for affected families.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.