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Recurrent rare copy number variants increase risk for esotropia


Whitman, MC and Di Gioia, SA and Chan, W-M and Gelber, A and Pratt, BM and Bell, JL and Collins, TE and Knowles, JA and Armoskus, C and Pato, M and Pato, C and Shaaban, S and Staffieri, S and MacKinnon, S and Maconachie, GDE and Elder, JE and Traboulsi, EI and Gottlob, I and Mackey, DA and Hunter, DG and Engle, EC, for the Strabismus Genetics Research Consortium, Recurrent rare copy number variants increase risk for esotropia, Investigative Ophthalmology & Visual Science, 61, (10) Article 22. ISSN 1552-5783 (2020) [Refereed Article]

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Copyright Statement

Copyright 2020 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) License.

DOI: doi:10.1167/iovs.61.10.22


Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

Item Details

Item Type:Refereed Article
Keywords:esotropia, strabismus, copy number variant, CNV, genetics of strabismus
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Mackey, DA (Professor David Mackey)
ID Code:140397
Year Published:2020
Web of Science® Times Cited:3
Deposited By:Menzies Institute for Medical Research
Deposited On:2020-08-13
Last Modified:2020-09-18
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