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Dror Sharon, Lina Zelinger, Samer Khateb, Avigail Beryozkin, Liliana Mizrahi-Meissonnier, Samuel Jacobson, Eyal Banin; Whole Exome Sequencing as a Tool for Identification of Genes Causing Autosomal Recessive Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3348.
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© ARVO (1962-2015); The Authors (2016-present)
Over 200 genes are known or suspected to cause inherited retinal diseases, and the number is likely to rise within the coming years. This is mainly due to next generation sequencing (NGS) techniques and whole exome sequencing (WES) in particular. The aim of this study is to use WES to identify the genetic cause of autosomal recessive (AR) retinitis pigmentosa (RP) in 30 Israeli index cases.
Patients with ARRP who agreed to participate in the study were recruited at Hadassah medical center. Clinical data included family history, ocular examination and imaging. Genomic DNA was extracted from blood samples and analyzed using Affymetrix whole genome single nucleotide polymorphism (SNP) microarrays and/or WES (Otogenetics Corporation).
We selected for this study a set of 30 index cases with ARRP. The DNA sample of each patient was prescreened for all mutations known to cause retinal degeneration in the appropriate ethnic group. We obtained an average of about 50 million sequences per sample and assembled them to the reference human genome sequence. Each WES sample was initially analyzed to detect mutations in known retinal degeneration genes. In seven samples we have identified mutations, most of which are novel, in known RP genes (RP1, CNGA1, CNGB1, CYP4V2, C2orf71, RDH12, and ABCA4). In a nonconsanguineous family with three siblings affected by nonsyndromic RP, we identified compound novel mutations in the BBS2 gene known to cause Bardel-Biedl syndrome. In three additional families we identified likely disease causing mutations that are currently being evaluated. Interestingly, seven out of the 30 index cases carried single heterozygous null mutations in known disease-causing genes, that are unlikely to be the cause of disease but might affect disease severity. The analysis of the remaining exome samples is being performed mainly using homozygosity data obtained by whole genome SNP arrays.
We present here the first comprehensive WES analysis in Israeli and Palestinian patients with RP. Pre-screening for known founder mutations and the availability of homozygosity mapping data improve WES efficiency as a tool for identification of novel disease-causing genes.
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