September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Beyond the Exon: Variants in regulatory and non-coding regions play a functional role in the pathogenesis of inherited retinal disease
Author Affiliations & Notes
  • Evan Jones
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Justin Branch
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Ruifang Sui
    Ophthalmology, Peking Union Medical College, Beijing, China
  • Robert K Koenekoop
    Ocular Genetics Laboratory, McGill University, Montreal, Quebec, Canada
  • Fernanda Belga Ottoni Porto
    INRET - Clinica e Centro de Pesquisa, Belo Horizonte, Minas Gerais, Brazil
  • Aleksandar Milosavljevic
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Yumei Li
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Evan Jones, None; Justin Branch, None; Ruifang Sui, None; Robert Koenekoop, None; Fernanda Porto, None; Aleksandar Milosavljevic, None; Yumei Li, None; Rui Chen, None
  • Footnotes
    Support  RC is supported by grants from National Eye Institute (R01EY022356 and R01EY018571) and a grant from Foundation Fighting Blindness (BR-GE-0613-0618-BCM). RKK is supported by the Foundation Fighting Blindness Canada and CIHR.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2062. doi:
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      Evan Jones, Justin Branch, Ruifang Sui, Robert K Koenekoop, Fernanda Belga Ottoni Porto, Aleksandar Milosavljevic, Yumei Li, Rui Chen; Beyond the Exon: Variants in regulatory and non-coding regions play a functional role in the pathogenesis of inherited retinal disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2062.

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

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Abstract

Purpose : Increasing evidence supports the hypothesis that non-coding variants may play a functional role in inherited retinal diseases, such as Stargardt disease (STGD). STGD is a recessive macular degenerative disease caused by mutations in the gene, ABCA4. The purpose of this work is to characterize the pathogenic role of non-coding variants in STGD patients. We hypothesize that STGD patients enriched for single exonic mutations in ABCA4 also harbor non-coding variants that play a functional role in contributing to disease.

Methods : Tissue-specific epigenetic profiling data was utilized to annotate functional non-coding regulatory regions, such as enhancers and suppressors in ABCA4. Targeted next-generation sequencing (NGS) was performed across the entire genomic locus of ABCA4 for 60 STGD individuals with a previously identified single exonic mutation in ABCA4. NGS data was aligned, processed and filtered against control datasets using an in-house custom pipeline. Non-coding rare variants identified in our annotated regulatory regions along with those predicted to affect splicing were tested for functional effects. These variants were functionally validated through in vitro cell line assays for their relative effects on gene expression and protein function.

Results : Analysis of tissue-specific epigenetic profiling data across the ABCA4 locus identified potential regulatory regions controlling ABCA4 expression. Through our NGS approach, targeting both introns and exons of ABCA4, we identified a number of recurrent variants within potential regulatory regions. We also identified a number of non-coding mutations predicted to disrupt splicing of ABCA4. We have functionally validated the role of non-coding splice-altering variants in ABCA4 and are validating the functional effects of additional recurrent variants within the characterized regulatory regions.

Conclusions : Through this work we show the role of non-coding variants in the functional dysregulation of ABCA4 in STGD patients. This research will help expand our understanding and ability to annotate and interpret non-coding variants that may contribute to disease and improve the rate of molecular diagnosis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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