June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Sequence analysis of 108 genes associated with non-syndromic inherited retinal diseases in 3,200 probands using molecular inversion probes
Author Affiliations & Notes
  • Muhammad Khan
    Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands
  • Perez-Carro Raquel
    Department of Genetics, Instituto de Investigación Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS-FJD, UAM), Madrid, Spain
    Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
  • Dror Sharon
    Departement of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • Robert K Koenekoop
    Departments of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada
  • Carlo Rivolta
    Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
  • Elfride De Baere
    Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  • Chris F Inglehearn
    Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, United Kingdom
  • Susanne Kohl
    Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
  • Christian P Hamel
    Institute for Neurosciences of Montpellier, University of Montpellier-University Hospital, Montpellier, France
  • Tamar Ben-Yosef
    The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  • Berta De la Cerda
    Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Sevilla, Spain
  • Daniel F Schorderet
    Institute for Research in Ophthalmology (IRO), Sion, Switzerland
  • Sandro Banfi
    Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
  • Carmen Ayuso
    Department of Genetics, Instituto de Investigación Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS-FJD, UAM), Madrid, Spain
    Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
  • Frans P Cremers
    Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Muhammad Khan, None; Perez-Carro Raquel, None; Dror Sharon, None; Robert Koenekoop, None; Carlo Rivolta, None; Elfride De Baere, None; Chris Inglehearn, None; Susanne Kohl, None; Christian Hamel, None; Tamar Ben-Yosef, None; Berta De la Cerda , None; Daniel Schorderet, None; Sandro Banfi, None; Carmen Ayuso, None; Frans Cremers, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2758. doi:
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      Muhammad Khan, Perez-Carro Raquel, Dror Sharon, Robert K Koenekoop, Carlo Rivolta, Elfride De Baere, Chris F Inglehearn, Susanne Kohl, Christian P Hamel, Tamar Ben-Yosef, Berta De la Cerda, Daniel F Schorderet, Sandro Banfi, Carmen Ayuso, Frans P Cremers; Sequence analysis of 108 genes associated with non-syndromic inherited retinal diseases in 3,200 probands using molecular inversion probes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2758.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Non-syndromic inherited retinal diseases (IRDs) display an enormous allelic and genetic heterogeneity as ~140 genes have been implicated. The purpose of this study was to develop a comprehensive genetic sequencing method that can tackle the extreme genetic heterogeneity of IRDs in a cost-effective manner.

Methods : The target enrichment procedure was based upon molecular inversion probes (MIPs). 6,200 MIPs captured ~1,600 exons and flanking intronic regions of 108 IRD-associated genes as well as selected deep-intronic variants and deletion-breakpoints. The individual captured targets were bar-coded, pooled (on average 120 samples), and sequenced on a NextSeq500 apparatus. The paired end reads were mapped to genomic reference; thereafter variant calling and annotation was performed using an in-house pipeline.

Results : Sequencing data was obtained for ~3,200 IRD probands. Putative causal variants were identified in 47% (n=1500) of the cases and the analysis is still ongoing for another 25% of the cases. Many IRD cases previously were prescreened for variants in IRD-associated genes. In DNA samples from 150 unscreened probands, we identified (likely) causal variants in 106 cases (71%). In many IRD cases novel genotype-phenotype correlations were identified, for which clinical data are being re-investigated. About 40 isolated and 26 autosomal recessive cases were found to have variants in genes associated with autosomal dominant (ad) RD. In 4 of these cases for whom parent DNAs were available, de novo variants were found. Similarly, 15 isolated male and 4 female probands were found to carry the likely causal variant in an X-linked gene.

Conclusions : Employing the MIPs technology, we were able to provide a genetic diagnosis for ~1,500 individuals with IRDs. The results of our study strongly advocate the use of a broad gene panel to identify the causal variants in IRDs without subselection based upon the presumed inheritance pattern & clinical subtypes. Clearly there is a huge unmet need for a cost-effective genotyping tool for IRD cases. Patients can now receive a much more accurate clinical prognosis and genetic counseling, which is particularly important for (isolated) RD cases carrying autosomal dominant or X-linked defects. Our results also will enable the recruitment of patients for gene augmentation therapies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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