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T. L. McGee, A. I. Den Hollander, S. Mukai, E. L. Berson; Identification of Genetic Defects Causing Recessive Retinal Degeneration Aided by Homozygosity Mapping in Consanguineous Families. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1694.
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© ARVO (1962-2015); The Authors (2016-present)
Hereditary forms of retinal degeneration including diseases such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Usher syndrome, and cone-rod dystrophy are genetically heterogeneous. The genetic causes of many cases of recessive retinal degenerations remain unidentified. The purpose of this study is to use homozygosity mapping in consanguineous families to identify novel genes or mutations in recessive retinal degenerations.
We ascertained 7 consanguineous families with two or more affected family members. In addition, we identified two non-consanguineous families with two affected individuals in which all four grandparents of the index patient shared the same ethnic background. The families include 3 with LCA, 3 with autosomal recessive RP (ARRP), and 1 each with either cone-rod dystrophy, Usher syndrome type I, or probable Goldmann-Favre syndrome. We performed a genome-wide screen of single nucleotide polymorphisms (SNPs) using The GeneChip Human Mapping 250K Array (Affymetrix) for all affected family members. Data from the SNP microarray was analyzed using the software dCHIP to identify all regions of homozygosity shared by affected siblings.
One to 8 shared homozygous genomic regions were identfied among these families with sizes ranging from 3.4 to 52Mb. A previously described retinal degeneration gene existed within a homozygous region in 6 of these families; CRB1 in 2 LCA families and an Usher family, LRAT in one ARRP family, CNGB1 in one ARRP family, and NR2E3 in the probable Goldmann-Favre family. The other 3 families do not have known retinal degeneration genes within the homozygous intervals. Sequencing of the CRB1 gene revealed the previously described mutation Val578Glu in one LCA family, a novel mutation Ser487Pro in the other LCA family, and no mutation in the Usher family. Sequencing of NR2E3 revealed the mutation IVS1-2A>C confirming the diagnosis of Goldmann-Favre syndrome in this family. No mutation was found in the LRAT gene in the ARRP family. Sequencing of CNGB1 in one family is ongoing.
Using homozygosity mapping we identified 2 families with mutations in CRB1 and one family with a mutation in NR2E3. The CRB1 mutation Ser487Pro is novel. At least 5 of the families do not carry a mutation in a known gene and are likely to harbor mutations in novel disease genes. Sequencing of candidate genes in the detected homozygous regions is ongoing.
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