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Kristof Van Schil, Françoise Meire, Thomy de Ravel, Bart Leroy, Hannah Verdin, Frauke Coppieters, Elfride De Baere; Identification of Novel Homozygous Deletions in Consanguineous Pedigrees as a Shortcut to Candidate Gene Discovery in Retinal Dystrophies. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1309.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the underlying genetic cause in 25 pre-screened consanguineous families diagnosed with autosomal recessive retinitis pigmentosa (ARRP) or Leber congenital amaurosis (LCA) using identity-by-descent (IBD) mapping. To demonstrate the power of mapping of homozygous deletions as a shortcut to candidate gene identification in retinal dystrophies (RDs).
IBD mapping was performed by genome-wide SNP chip analysis (HumanCytoSNP-12, Illumina). For IBD data analysis we integrated PLINK with arrayCGHbase, a platform for data analysis of microarray based comparative genome hybridization. Deletions were confirmed and fine-mapped by conventional PCR. Segregation analysis was performed by qPCR (LightCycler, Roche; qBase Plus, Biogazelle).
Homozygous deletions were identified in 3 out of 25 families. The first deletion (133 kb) was found in an ARRP patient and removes the first non-coding exon of the known gene EYS. The second deletion (112 kb) was found in a patient with early-onset RD. It disrupts the last 3 exons of RERG and the lncRNA RERG-AS1. The third one (416 kb) is a partial deletion of GRID2, found in a patient with LCA. It leads to an in-frame deletion (p.Gly30_Glu81del). All of them were located in the one but largest IBD region. The deletions could be confirmed and segregation could be demonstrated. They were absent in our local database containing more than 3000 subjects. Non-coding deletions of EYS have not yet been described. As to the RERG and GRID2 genes, both are regulated by the transcription factor CRX (Corbo et al., 2010). Although the function of RERG remains unclear, it was found in several retinal transcriptome datasets (Gamsiz et al., 2012 and Booij et al., 2009). GRID2 encodes a neurotransmitter receptor that plays an important role in the brain, a homozygous mutation in mouse was found to be lethal (Zuo et al., 1997). The in-frame GRID2 deletion found here might represent a hypomorphic allele leading to a milder phenotype. Further characterization and functional validation of these deletions is underway.
This study revealed involvement of a homozygous 5’UTR deletion of EYS in ARRP, and uncovered RERG and GRID2 as two potential novel candidate genes for RD. We demonstrated that homozygous deletion detection in consanguineous families might be a powerful approach for gene discovery of RDs.
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