Identifying Novel Genetic Causes of Retinal Dystrophy in the Pakistani Population

Abstract

Purpose: : At least 25 genes have been identified for autosomal recessive retinitis pigmentosa (arRP), which account for ~50% of all cases. Little is known about the causes of arRP in the Pakistani population. Identifying the genetic causes in this population will facilitate disease prognosis and genetic counseling and ultimately will aid in developing treatments for RP.

Methods: : We ascertained 271 patients with arRP or allied disease and their relatives from 45 families in Pakistan. Genomic DNA from the affected individuals was analyzed using 6K or 10K SNP arrays. On average, the SNP data analysis revealed 4 homozygous regions per family each encompassing 4-12 Mb. Microsatellite markers were used to confirm and narrow down the regions in all family members. Sequence analysis was performed to analyze candidate genes for mutations

Results: : In 12 families, homozygous regions were present encompassing known retinal disease genes. Based on the genetic data the families were revisited to confirm the disease status. Thus far, novel mutations were identified in CNGA3 and CNGB3 in two achromatopsia families, and in GRK1 in a family with Oguchi’s disease. In arRP families, novel mutations have been identified in CNGB1, CRB1, EYS, and PDE6B, while a known mutation was found in RHO. In other families, novel loci with significant LOD-scores were identified in which no known arRP gene is located. Candidate gene analysis to find the novel arRP genes is currently ongoing

Conclusions: : Thus far we identified mutations in known retinal disease genes in 40% of families of the Pakistani cohort. These findings indicate that homozygosity mapping in the Pakistani population is a powerful tool, not only to identify novel mutations in known arRP genes, but also to identify novel regions and genes involved in arRP

Keywords: gene mapping • retinal degenerations: hereditary • mutations