June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Disease-causing mutations in a cohort of autosomal dominant RP (adRP) families without detectable mutations in known adRP genes
Author Affiliations & Notes
  • Lori S Sullivan
    Human Genetics Center SPH, The Univ. of Texas HSC at Houston, Houston, TX
  • Sara J Bowne
    Human Genetics Center SPH, The Univ. of Texas HSC at Houston, Houston, TX
  • Susan H. Blanton
    Miami Institute for Human Genomics, Miller School of Medicine, Univ. of Miami, Miami, FL
  • Daniel C. Koboldt
    The Genome Institute, Washington Univ. School of Medicine, St. Louis, FL
  • Richard K. Wilson
    The Genome Institute, Washington Univ. School of Medicine, St. Louis, FL
  • Rui Chen
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
  • Feng Wang
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
  • Dianna K H Wheaton
    Retina Foundation of the Southwest, Dallas, TX
  • David G Birch
    Retina Foundation of the Southwest, Dallas, TX
  • Stephen P Daiger
    Human Genetics Center SPH, The Univ. of Texas HSC at Houston, Houston, TX
    Ruiz Dept. of Ophthalmology and Visual Science, The Univ. of Texas HSC at Houston, Houston, TX
  • Footnotes
    Commercial Relationships Lori Sullivan, None; Sara Bowne, None; Susan Blanton, None; Daniel Koboldt, None; Richard Wilson, None; Rui Chen, None; Feng Wang, None; Dianna Wheaton, None; David Birch, None; Stephen Daiger, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2875. doi:https://doi.org/
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    • Get Citation

      Lori S Sullivan, Sara J Bowne, Susan H. Blanton, Daniel C. Koboldt, Richard K. Wilson, Rui Chen, Feng Wang, Dianna K H Wheaton, David G Birch, Stephen P Daiger; Disease-causing mutations in a cohort of autosomal dominant RP (adRP) families without detectable mutations in known adRP genes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2875. doi: https://doi.org/.

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

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Abstract

Purpose: To determine the cause of disease in a cohort of 64 families with a diagnosis of adRP but without disease-causing mutations detected using panel-based Sanger sequencing and retinal-capture next-generation sequencing (NGS).

Methods: Unrelated probands in a cohort of 266 families with a diagnosis of adRP were tested by Sanger sequencing for mutations in known adRP genes and RPGR and RP2; probands without mutations were tested with retinal-capture NGS. Pathogenic mutations were identified in 76% of families. The remaining 64 families without detectable mutations were analyzed by a variety of methods including linkage mapping in suitably-large families, and whole-exome and whole-genome NGS. Potential disease-causing variants were tested in a panel of 200 adRP families not part of the original cohort.

Results: Linkage mapping localized the disease gene in 6 families to one or a few chromosomal sites, largely non-overlapping sites across families. Known retinal-disease genes in or contiguous to each linkage region were excluded by high-resolution linkage testing and/or sequencing. Whole-exome NGS was conducted in 10 or more affected members of the 6 families and in fewer members of 12 other families. Whole-genome NGS was conducted in 2 families. Rare variants tracking with disease were evaluated by bioinformatic methods and lists of potentially-pathogenic variants, and variants of unknown significance, were shared with other laboratories. A novel, dominant-acting mutation in RPE65 was identified in one family and a disease-causing mutation in a new adRP gene, HK1, was found in a second large family. From 10 to 100 rare variants were detected in the linkage regions of the remaining mapped families and numerous potentially-deleterious variants are tracking with disease in the smaller families. None of the rare variants detected are clearly pathogenic.

Conclusions: Mutations in at least 21 genes are known to cause adRP; linkage mapping in families without mutations in known genes indicates that several adRP genes remain to be found. Whole-exome and whole-genome NGS are powerful tools for finding disease-causing mutations in retinal disease genes but establishing pathogenicity of rare variants in families without mutations in known genes is a difficult problem. Data sharing between laboratories with similar research interests is a helpful adjunct to genetics research.

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