Dataset Information

The molecular basis of retinal dystrophies in pakistan.

ABSTRACT: The customary consanguineous nuptials in Pakistan underlie the frequent occurrence of autosomal recessive inherited disorders, including retinal dystrophy (RD). In many studies, homozygosity mapping has been shown to be successful in mapping susceptibility loci for autosomal recessive inherited disease. RDs are the most frequent cause of inherited blindness worldwide. To date there is no comprehensive genetic overview of different RDs in Pakistan. In this review, genetic data of syndromic and non-syndromic RD families from Pakistan has been collected. Out of the 132 genes known to be involved in non-syndromic RD, 35 different genes have been reported to be mutated in families of Pakistani origin. In the Pakistani RD families 90% of the mutations causing non-syndromic RD and all mutations causing syndromic forms of the disease have not been reported in other populations. Based on the current inventory of all Pakistani RD-associated gene defects, a cost-efficient allele-specific analysis of 11 RD-associated variants is proposed, which may capture up to 35% of the genetic causes of retinal dystrophy in Pakistan.

SUBMITTER: Khan MI

PROVIDER: S-EPMC3978518 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The molecular basis of retinal dystrophies in pakistan.

Khan Muhammad Imran MI Azam Maleeha M Ajmal Muhammad M Collin Rob W J RW den Hollander Anneke I AI Cremers Frans P M FP Qamar Raheel R

Genes 20140311 1

The customary consanguineous nuptials in Pakistan underlie the frequent occurrence of autosomal recessive inherited disorders, including retinal dystrophy (RD). In many studies, homozygosity mapping has been shown to be successful in mapping susceptibility loci for autosomal recessive inherited disease. RDs are the most frequent cause of inherited blindness worldwide. To date there is no comprehensive genetic overview of different RDs in Pakistan. In this review, genetic data of syndromic and no ...[more]

PMID: 24705292

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Project description:Most diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs.

Dataset Information

The molecular basis of retinal dystrophies in pakistan.

Publications

The molecular basis of retinal dystrophies in pakistan.

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