September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Inherited optic atrophy gene discovery using whole exome sequencing.
Author Affiliations & Notes
  • John Simmons Borchert
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Isao Nakata
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Daniel Navarro-Gomez
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Maria Janessian
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Elizabeth Delbono
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Janey L Wiggs
    Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   John Borchert, None; Isao Nakata, None; Daniel Navarro-Gomez, None; Maria Janessian, None; Elizabeth Delbono, None; Janey Wiggs, None
  • Footnotes
    Support  P30EY014104 and an Award from the Alcon Research Institute
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5063. doi:
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    • Get Citation

      John Simmons Borchert, Isao Nakata, Daniel Navarro-Gomez, Maria Janessian, Elizabeth Delbono, Janey L Wiggs; Inherited optic atrophy gene discovery using whole exome sequencing.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5063.

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

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Abstract

Purpose : Inherited disorders of the optic nerve cause significant visual impairment in children and adults. Approximately 50% of patients with inherited forms of optic neuropathy have mutations in OPA1, mitochondrial DNA (LHON) or other known genes. The genetic etiology of the disease is unknown for the remaining 50% of patients. Whole exome sequencing (WES) has been shown to be a useful approach for discovery of genes responsible for diseases with mendelian inheritance, such as inherited optic atrophy. The purpose of this study is to use exome sequencing to identify novel inherited optic atrophy genes.

Methods : Genomic DNA purified from optic atrophy probands were initially screened for mutations using our diagnostic panel test that includes 13 optic atrophy genes (including OPA1, OPA3, WFS1) and mitochondria DNA (GEDi test). 10 probands and 5 family members who did not have mutations in any of the known genes included in our diagnostic panel underwent whole exome sequencing (WES) using Sure Select V4+UTR+Mito Agilent (71.4 Mb target region) exon capture followed by paired end sequencing on the Illumina Hi-Seq. Sequence data was analyzed by our Ocular Genomics Institute (OGI) pipeline and annotated variants were filtered to select alleles with pathogenic features including: rare (less than .1% in population databases); evolutionarily conserved (GERP > 2.0); nonsynonomous; in silico pathogenicity (Polyphen2 and SIFT); genetic disease model (autosomal dominant, autosomal recessive or mitochondrial) and ocular expression.

Results : High quality whole-exome sequence data (75X mean coverage and 99% with >20X coverage) was obtained for all 10 probands and 5 family members. After filtering, 10 potentially disease causing mutations were identified in 5 different genes: SYDE2, HELZ2, BPIFB3, CLEC5A, and POLR3GL. Further evaluation of candidate variants in other pedigree members (if available) is currently ongoing. Variants of interest will be examined for functional effects using morpholino-mediated knockdown in zebrafish.

Conclusions : Using whole exome sequencing, we have identified novel candidate genes responsible for inherited optic atrophy. Further studies investigating segregation of putative disease-causing alelles in affected families and functional studies in zebrafish will be necessary to establish causality.

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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