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Elfride De Baere, Steve Lefever, Francoise Meire, Kristof Van Schil, Elly Devlieghere, Bart P. Leroy, Frauke Coppieters; Molecular Diagnosis Of Autosomal Recessive Retinal Dystrophies By Homozygosity Mapping With SNP Arrays. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5377.
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Homozygosity or identity-by-descent (IBD) mapping has been instrumental in gene discovery of several autosomal recessive (AR) retinal dystrophies (RDs). The increasing use of genomewide SNP chips makes IBD mapping an accessible tool in a clinical context. The goal of this study is to demonstrate the efficacy of SNP chip based IBD mapping as a molecular diagnostic tool in consanguineous families with a variety of RDs.
In total, 35 patients out of 29 families underwent IBD mapping using 250,000 SNP chips. Twenty probands were diagnosed with one of the following retinal phenotypes: Leber Congenital Amaurosis (LCA) (6), early-onset retinal dystrophy (EORD) (2), AR retinitis pigmentosa (ARRP) (9) or AR cone-rod dystrophy (ARCRD) (3). In addition, nine probands presented with a syndromic RD: Senior-Loken syndrome (SLS) (2); LCA with mental retardation (MR) (2) or deafness (1); Usher syndrome type I (1) and II (2) and ARRP in combination with mild MR, growth hormone defect and acromelic dysplasia (1). Candidate genes associated with RDs located within major IBD regions were screened for mutations by Sanger sequencing. In patients in whom a mutation was found the clinical record was revisited.
IBD mapping followed by sequencing of one or two candidate genes revealed homozygous sequence variants in nine families. New variants were found in the following genes: RDH12 (3), IQCB1 (3), USH2A, ABCA4, CNNM4. The clinical diagnosis was revisited in all families in which the molecular cause was elucidated. A reappraisal of the clinical diagnosis was made in patients with mutations in RDH12 and CNNM4.
In our study we applied IBD mapping as a diagnostic tool in 29 families segregating RDs. Following SNP genotyping and sequencing of only one to two candidate genes per proband, the causal mutation was identified in 9 families (31%) so far, thereby overcoming the need for laborious gene-to-gene testing of all known disease genes and the need for a well established phenotype prior to testing. Indeed, we demonstrated that IBD mapping allowed the identification of disease genes that would not have been selected by routine first pass screening based on the patient’s initial clinical diagnosis. Finally, IBD mapping can also be used in families with a single affected individual.
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