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D. Sharon, L. Bida, D. Bandah, T. Strom, S. Merin, E. Banin; Identification of Novel Retinal Degeneration Loci in Consanguineous Israeli and Palestinian Families With Retinal Disease. Invest. Ophthalmol. Vis. Sci. 2008;49(13):6094. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The Israeli population is highly heterogeneous and served as a good source for the identification of genes causing autosomal recessive disease in many studies. Our purpose is to take advantage of the high rate of consanguinity and the large family size present in our population to identify novel genes causing hereditary retinal degenerative diseases.
Clinical evaluation of Israeli and Palestinian patients included detailed family history, full ophthalmologic exam, and full-field electroretinography (ERG). Affymetrix whole-genome 10K and 250K single nucleotide polymorphism (SNP) arrays were used to genotype markers. Data analysis was performed aiming to identify the largest homozygous regions in each family. Additional markers within these regions were genotyped by sequencing analysis. Mutation analysis was performed by direct sequencing of PCR products.
We used the 10K SNP arrays to genotype 63 patients from 40 different families that belong to different genetic backgrounds (30 Muslim, 23 Jewish, 8 Bedouin, and 2 Christian-Arab patients). On average, each tested patient was homozygote for 68.4% of genotyped markers and had 4 homozygous genomic loci which were larger than 20Mb. A search for large homozygous regions in affected individuals revealed 18 families in which a known disease-causing gene is located within one of the two largest regions. Mutation analysis of these candidate genes revealed pathogenic mutations in four families. Homozygous regions which are likely to harbor novel retinal degeneration genes were identified in 20 of the families. For example, patients with cone-rod degeneration from two families had large homozygous regions in the vicinity of the CORD9 locus: a Tunisian Jewish family and a Muslim family each with 3 affected siblings. An in-depth analysis of this region using 250k SNP array resulted in the identification of a recombination event which further reduced the interval size to only 3Mb. Two additional families, including three affected siblings from a Moroccan Jewish family with LCA and a patient from a Muslim family were found to share a 57Mb homozygous region on chromosome 9p21-q21. We are currently evaluating the involvement of candidate genes within these genomic regions.
Our study emphasizes the potential of studying the Israeli and Palestinian populations using homozygosity analysis for the identification of novel retinal degeneration genes.
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