Genetic & Molecular Basis of Inherited Visual Disorders

Abstract

The inherited visual disorders are leading cause of blindness all over the world. In Pakistan, where consanguinity is common, high prevalence of genetically transmitted visual disorders is a serious health problem from socio-economic aspect. The present study was aimed to investigate the genetic and molecular basis of various inherited visual disorders in Pakistani population. For this purpose, we enrolled Twenty seven families suffering from Primary Congenital Glaucoma, Stargardt disease and Congenital Cataract from different cities of Sindh province. Blood samples were obtained from affected as well as normal individuals from all enrolled families and detailed medical history and ophthalmological examination were carried out. All families were first subjected to genotyping to known/reported loci or genes for Primary Congenital Glaucoma (PCG), Stargardt disease and Congenital Cataract. Whole Exome Sequencing (WES) was done for the families found not linked to any known locus/gene and candidate variants were subjected to direct Sanger sequencing for segregation with the disease phenotype. Seventeen families with PCG were enrolled for present study. Thirteen PCG families were found linked to CYP1B1 gene. Sequencing further revealed two novel mutations in CYP1B1i.e. p.G36D and deletion of 12 bp (p.G67-A70del) in PCG-08 and PCG-09 respectively. p.R390H was found in eight PCG affected families whereas p.E229K and p.R290fs*37 (c.868_869insC) was found once in two families. p.A115P was found in one family with four phenotypically normal homozygotes as well most probably due to either non-penetrance or reduced penetrance of CYP1B1. Four families remained unlinked to any reported locus or gene for PCG. Five Stargardt disease affected families and five families with Congenital Cataract were screened for linkage to known or common loci/genes. After excluding linkage to reported genes, WES for two Stargardt disease families revealed a novel gene ARL3, which has not been reported earlier. Likewise we carried out WES for a single congenital cataract and it was found linked to INPP5K, a novel gene and has recently been reported in association with syndromic form of congenital cataract in 2017. xvii In brief, the study reports CYP1B1 as most common mutated gene for patients with PCG in our population. Two novel mutations, a missense and a deletion in CYP1B1 were found, in addition to already reported mutations in other PCG families whereas a novel gene (ARL3) was identified in association with Stargardt disease. In Congenital Cataract, INPP5K (a novel gene when it was first identified in November, 2016) was found to be segregated with disease phenotype. All these novel findings are suggestive of genetic heterogeneity of Pakistani population for inherited visual disorders and genetic factors responsible for corresponding phenotype. The data may be beneficial for public awareness and genetic screening of our population to improve the prognosis of corresponding genetic disorder by early diagnosis. In addition, the findings of this thesis may contribute to already existing data on inherited visual disorders especially when no significant work in this regard has been carried out in people of Sindh province of Pakistan.