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Lonneke Haer-Wigman, L. I. van den Born, Caroline C W Klaver, Carel C B Hoyng, Dorien Lugtenberg, Frans Cremers, Lies Hoefsloot, Wendy van Zelst-Stams, Helger Yntema; Exome sequencing in a diagnostic setting identifies a genetic cause in >54% of the inherited retinal disease patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1265.
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© ARVO (1962-2015); The Authors (2016-present)
In the Netherlands ~7,000 individuals are visually impaired due to inherited retinal diseases (IRDs). It is difficult to determine the genetic cause in patients with IRDs, due to high genetic heterogeneity. The aim of this study was to determine whether the genetic cause of persons with IRDs can be detected efficiently and with a high yield using whole exome sequencing (WES) in a diagnostic setting.
We performed WES using the Solid 5500XL or Illumina HiSeq2000 platform in 194 IRD probands. In 13% of the cases extra-ocular signs were present, for instance hearing loss. In the first step of WES analysis, variants in IRD-associated genes were investigated (https://sph.uth.edu/retnet/). When no causative mutation was identified, a second step was performed in which the whole exome was analyzed using stringent selection criteria for sequence variants: truncating variants, splice site variants at intronic positions -2, -1, +1, +2 and missense variants with a PhyloP score >3.5.
Sequence and copy number variant analysis in the panel of IRD genes allowed us to identify causal variants in 54% of cases. Causal variants were detected in 49 different IRD genes. The USH2A gene was most frequently the causative gene in the solved cases(17%); all other genes had a causative mutation frequency of <7%. In 54% of the cases known pathogenic, truncating or splice site (intronic positions -1, -2, +1, +2) mutations were detected, in other cases segregation analysis was desirable to determine whether the detected mutations were indeed disease-causing. In several cases, we identified new phenotype-genotype correlations, for example ABDH12 mutations were identified in a non-syndromic cone dystrophy patient. The analysis of genes not yet known to be implicated in IRDs of the second step revealed mutations in MFSD8 and POC1B, very recently implicated in non-syndromic cone dysfunctions, and mutations in VPS13B, implicated in Cohen syndrome. In addition, in an achromatopsia patient, homozygous mutations were detected in the NDGR4 gene. This gene is not associated with IRD as far as we know.
Through WES analysis in a diagnostic setting we detected the genetic cause of IRDs in more than half of the cases by analyzing known IRD-associated genes. In a second step new IRD candidate genes were detected which underlie IRDs in an additional 5-10% of the patients.
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