June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Application of Whole-Exome and Retinal-Capture Next-Generation DNA Sequencing to Identify Disease-Causing Mutations in Families with a Diagnosis of Autosomal Dominant Retinitis Pigmentosa
Author Affiliations & Notes
  • Stephen Daiger
    Human Genetics Center, School of Public Health, The Univ. of Texas Health Science Center, Houston, TX
  • Lori Sullivan
    Human Genetics Center, School of Public Health, The Univ. of Texas Health Science Center, Houston, TX
  • Sara Bowne
    Human Genetics Center, School of Public Health, The Univ. of Texas Health Science Center, Houston, TX
  • George Weinstock
    The Genome Institute, Washington University, St. Louis, MO
  • Daniel Koboldt
    The Genome Institute, Washington University, St. Louis, MO
  • Rui Chen
    Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
  • John Heckenlively
    Kellogg Eye Center, Univ. of Michigan, Ann Arbor, MI
  • Kari Branham
    Kellogg Eye Center, Univ. of Michigan, Ann Arbor, MI
  • David Birch
    Retina Foundation of the Southwest, Dallas, TX
  • Dianna Wheaton
    Retina Foundation of the Southwest, Dallas, TX
  • Footnotes
    Commercial Relationships Stephen Daiger, None; Lori Sullivan, None; Sara Bowne, None; George Weinstock, None; Daniel Koboldt, None; Rui Chen, None; John Heckenlively, None; Kari Branham, Arctic DX (P); David Birch, Acucela (C), QLT (C), Neurotech, USA (C); Dianna Wheaton, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4974. doi:
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      Stephen Daiger, Lori Sullivan, Sara Bowne, George Weinstock, Daniel Koboldt, Rui Chen, John Heckenlively, Kari Branham, David Birch, Dianna Wheaton; Application of Whole-Exome and Retinal-Capture Next-Generation DNA Sequencing to Identify Disease-Causing Mutations in Families with a Diagnosis of Autosomal Dominant Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4974.

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

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Abstract

Purpose: To detect disease-causing mutations in families with a diagnosis of autosomal dominant retinitis pigmentosa (adRP), focusing on genes known to cause inherited retinal diseases, using whole-exome next-generation sequencing (NGS) and retinal-capture NGS.

Methods: Families were selected from a cohort of 260 with a diagnosis of adRP and 3 affected generations and affected females, or two generations with male-to-male transmission. The families were previously screened for common mutations by Sanger sequencing. Coding exons and flanking intron-exon junctions of all known RetNet genes and candidate genes were targeted for NGS. Testing was either 1.) whole-exome NGS using Agilent SureSelect liquid-capture probes and the Illumina platform, focusing analysis on 190 retinal disease genes, 2.) targeted liquid-capture and NGS of coding regions of 160 retinal disease genes, or 3.) both. Families tested included positive controls with known mutations and families without a previously-identified mutation. Mutations detected by NGS were confirmed by Sanger sequencing.

Results: Probands and additional family members from 87 families, including controls, were tested by one or both methods. Of 22 families tested by whole-exome NGS, mutations were found in 7 (32%). Of 18 control families with known mutations tested by retinal-capture NGS, mutations were found in 17. (A large deletion in PRPF31 was not detected). Of 69 families without known mutations tested by retinal-capture NGS, mutations were found in 10 (15%). In summary, of a total of 76 families whose mutations were not known prior to NGS, mutations were found in 17 (22%). Several of these mutations are in genes not currently associated with autosomal dominant disease.

Conclusions: Targeted retinal-gene capture or focused retinal-gene analysis following whole-exome NGS, are reliable, efficient methods for detecting disease-causing mutations in families with dominant retinitis pigmentosa. Based on a variety of methods, mutations in coding exons or intron-exon junctions of known retinal disease genes (RetNet genes) account for at least 72% of families in our cohort with dominant RP.

Keywords: 696 retinal degenerations: hereditary • 604 mutations • 537 gene screening  
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