September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Whole Exome Sequencing Identifies Mutations in GNB3 to Cause a Novel Congenital Stationary Night Blindness Phenotype
Author Affiliations & Notes
  • Ajoy Vincent
    Ophthalmology and Visual Sciences , Genetics and genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
    Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
  • Erika Tavares
    Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  • Isabelle S Audo
    INSERM, UPMC, CHNO, Paris, France
    University College of London, London, United Kingdom
  • jason maynes
    Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
    Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada
  • Shuning Li
    Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  • Christelle Michiels
    INSERM , Paris, France
  • Anupreet Tumber
    Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
  • Heather Macdonald
    Ophthalmology and Vision Sciences, Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
    Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  • Chelsea Roadhouse
    Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
  • Christina Zeitz
    INSERM, UPMC, CHNO, Paris, France
  • Elise Heon
    Ophthalmology and Visual Sciences , Genetics and genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
    Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
  • Footnotes
    Commercial Relationships   Ajoy Vincent, None; Erika Tavares, None; Isabelle Audo, None; jason maynes, None; Shuning Li, None; Christelle Michiels, None; Anupreet Tumber, None; Heather Macdonald, None; Chelsea Roadhouse, None; Christina Zeitz, None; Elise Heon, None
  • Footnotes
    Support  University of Toronto McLaughlin Center Accelerator Grant 2014
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Ajoy Vincent, Erika Tavares, Isabelle S Audo, jason maynes, Shuning Li, Christelle Michiels, Anupreet Tumber, Heather Macdonald, Chelsea Roadhouse, Christina Zeitz, Elise Heon; Whole Exome Sequencing Identifies Mutations in GNB3 to Cause a Novel Congenital Stationary Night Blindness Phenotype. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : To identify the genetic cause underlying autosomal recessive congenital stationary night blindness (CSNB) in a family.

Methods : Ten of the 11 members in a three generation pedigree including 3 affected (2 siblings & maternal aunt) underwent detailed eye evaluation. Full-field electroretinogram (ERG) was done in 8 members. DNA was extracted from 11 members using classical methods. The proband (7 year old male) had been screened negative for mutations in the known CSNB genes by targeted next generation sequencing. Whole exome sequencing (WES) was performed on 2 trios in the family using Illumina Hi-Seq 2500 platform. On WES analysis, genes containing 2 rare non-synonymous coding or splicing variants (allele frequency <0.01) were prioritized in two affected; 13 genes were shared amongst the two fulfilling this criterion. Candidate genes were prioritized and variant validation & segregation analysis was performed by Sanger sequencing.

Results : The proband was compound heterozygous for an in-frame deletion (p.K57del) and a stop mutation (p.W338*) in GNB3. The affected aunt was homozygous for stop mutation (p.W338*). Both variants segregated with the disease phenotype in the family. Distance visual acuity was 20/30 or better in all affected; fundus was normal in all affected. Dim flash scotopic ERG (.01 cd.s.m-2) showed reduced (n=2; sib-ship) or absent (n=1; aunt) rod b-wave. Scotopic ERG to a bright flash (10 cd.s.m-2) showed electronegative response in all affected, consistent with rod ON-bipolar dysfunction. Photopic ERG to standard flash (3 cd.s.m-2) and long flash (150ms) showed selective cone ON-bipolar involvement in the sib-ship, and cone ON- & OFF-bipolar involvement in the aunt. All single heterozygous carriers of GNB3 (n=5) had normal eye exam & normal ERG. Forty cases of CSNB previously excluded for mutations in known genes, did not reveal pathogenic variations in GNB3.

Conclusions : This is the first study to implicate GNB3 in a retinal disease. The CSNB phenotype in the family is variable but novel, and show 2 subtypes: the milder subtype shows partial but selective ON-bipolar abnormality & the severe subtype shows complete ON-bipolar involvement with additional OFF-bipolar involvement. Phenotype variability noted in the family may be mutation specific. The milder human phenotype resemble Gnb3 knock out mice models that show partial ON-bipolar pathway abnormality.

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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