July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Rare Copy Number Variants Increase Risk for Esotropia
Author Affiliations & Notes
  • Mary Whitman
    Ophthalmology, Boston Childrens Hospital, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Silvio Alessandro Di Gioia
    Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wai-Man Chan
    Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Alon Gelber
    Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sherin Shaaban
    Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sandra Staffieri
    Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
    Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia
  • Sarah MacKinnon
    Ophthalmology, Boston Childrens Hospital, Boston, Massachusetts, United States
  • David A Mackey
    Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
  • David G Hunter
    Ophthalmology, Boston Childrens Hospital, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Elizabeth Engle
    Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
    Ophthalmology, Boston Childrens Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Mary Whitman, None; Silvio Alessandro Di Gioia, None; Wai-Man Chan, None; Alon Gelber, None; Sherin Shaaban, None; Sandra Staffieri, None; Sarah MacKinnon, None; David Mackey, None; David Hunter, None; Elizabeth Engle, None
  • Footnotes
    Support  NEI 5K08EY027850, Children’s Hospital Ophthalmology Foundation [Faculty Discovery Award], NIH R01EY015298, NIH R01EY027421, Howard Hughes Medical Institute
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1769. doi:https://doi.org/
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    • Get Citation

      Mary Whitman, Silvio Alessandro Di Gioia, Wai-Man Chan, Alon Gelber, Sherin Shaaban, Sandra Staffieri, Sarah MacKinnon, David A Mackey, David G Hunter, Elizabeth Engle; Rare Copy Number Variants Increase Risk for Esotropia. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1769. doi: https://doi.org/.

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

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Abstract

Purpose : Esotropia is the most common form of strabismus in European ancestry populations. Population, twin and family studies indicate a genetic predisposition, but no causative genes have been identified. Our recently published genome-wide association study (GWAS) identified a risk locus for non-accommodative esotropia in intron 1 of the WRB (tryptophan-rich basic protein) gene on chromosome 21. The risk SNP is differentially methylated and there is a skew toward paternal inheritance of the risk allele. Other neurological disorders, including Tourette syndrome, intellectual disability and autism, have recently been linked to DNA copy number variations (CNVs). We examined our cohort for rare CNVs, to determine if rare CNVs also contribute to esotropia.

Methods : Using the cohort of European ancestry esotropia patients included in the previous GWAS, we examined a subset of 1615 individuals with esotropia (both accommodative and non-accommodative) for CNVs and compared to 3922 publicly available controls. PennCNV and QuantiSNP were used to call CNVs from Illumina SNP chip data, for patients and controls. Only CNVs called by both programs, greater than 10kb and spanning 10 or more SNPs were included. Common CNVs and immunoglobulin regions, segmental duplications, centromeres and telomeres were excluded. Statistical comparisons were made using 1 million permutations in plink software. Significant CNVs were validated using digital droplet PCR (ddPCR).

Results : DNA duplications of regions of chromosomes 2, 4, 9, and 10 showed a significant association (p=1x10-6) with esotropia. Each duplication was validated in esotropia patients by ddPCR. 127 of the 1615 esotropia patients had one or more of these four duplications. These duplications encompass 23 genes, non-coding RNAs or pseudogenes (3 on chr2, 1 on chr4, 9 on chr9, 10 on chr10).

Conclusions : This is the first study to report associations of esotropia with rare DNA CNVs. Esotropia is likely inherited as a complex trait, with multiple genetic variants contributing to risk. These duplications may alter gene dosages and/or disrupt genes or regulatory regions at their insertion sites. Future studies of the genes and regulatory regions involved and disrupted by the DNA duplications should provide insight into the pathophysiology of esotropia.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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