Overview of genetic causes and identification of novel loci for retinal dystrophies in Pakistan

Abstract

Purpose: Inherited retinal dystrophies (iRD) are clinically and genetically heterogeneous disorders. In Pakistan the frequency of iRD is estimated to be 1 in 800 patients. For different iRD, 185 genes have been identified to date. Among these genes, 119 are linked to non-syndromic forms of the disease. In this study we aimed to elucidate the genetic causes of 17 iRD families and to provide a comprehensive genetic overview of all iRD that have been studied in Pakistan. The customary consanguineous nuptials in Pakistan underlies the frequent occurrence of autosomal recessive inherited disorders, including RD, and therefore homozygosity mapping has been the method of choice to map disease genes and loci.

Methods: DNAs of selected members from 17 arRD families were genotyped on single nucleotide polymorphism microarrays and the data were analyzed using an online homozygosity mapper tool. Sanger sequencing was carried out for genes previously associated with iRDs residing in the homozygous regions. In addition all published genetic data of Pakistani families with syndromic and non-syndromic iRDs was compiled.

Results: From a cohort of 41 randomly collected Pakistani iRD families, most of which show retinitis pigmentosa (RP), results for 17 are described in this study. In 8 families causal genetic defects have been identified while in another 9 consanguineous arRP families, novel genetic loci are implicated. A total of 65 studies were identified through a literature search that described genetic data of 156 iRD families of Pakistani origin.

Conclusions: Taking into consideration our previously published studies, we could genetically solve 32 of 41 (78%) families from our iRD cohort. Keeping in mind that a proportion of the elusive variants may reside deep intronic, we estimate that that >90% of genes underlying non-syndromic iRD has been identified. The inventory of all Pakistani iRD mutation data showed that Pakistani families with arRD have been instrumental in finding ten iRD-associated genes and have enabled the recognition of novel genotype-phenotype correlations for three genes. Ninety percent of mutations causing non-syndromic RD and all mutations causing syndromic forms in Pakistani families are population specific. We propose a cost-effective genetic test in which 50% of the most prevalent mutations can be tested by sequence analysis of 14 different amplicons in 10 different genes.

Keywords: 696 retinal degenerations: hereditary • 534 gene mapping • 539 genetics