Genetic Epidemiology of Congenital Cataracts and Autosomal Recessive Retinal Degenerations in Pakistan

Abstract

The National Eye Institute (NEI) of the United States, the Centre for Excellence in Molecular Biology (CEMB), and Allama Iqbal Medical College in Lahore, Pakistan collaborate in an ongoing international genetic collaboration to identify the genes and mutations responsible for retinitis pigmentosa and congenital cataracts in the Pakistani population. To date, we have recruited a total of 115 consanguineous families with autosomal recessive congenital cataract (arCC) and 138 consanguineous families with autosomal recessive retinal dystrophy (arRD). After undergoing linkage analysis and sequencing of candidate genes in identified linked regions, unmapped families were subjected to homozygosity exclusion mapping by screening closely flanking microsatellite markers at known candidate gene/loci, followed by Sanger sequencing of the nearby candidate gene if homozygosity was present. Analysis of these families has resulted in identification of disease loci or genes causing disease in 42 families with arCC and 96 families with (RD), including novel disease-causing genes in 5 of these families. Since selection of both families and candidate loci was unbiased, this approach allowed an accurate estimate of the contributions of various genes to arCC and arRD in Pakistan. The causative genes remain unidentified in about 2/3 arCC families and 1/3 of arRD families in our study, making next-generation sequencing an ideal method for identification of new genes.