Recurrent Rare Copy Number Variants Increase Risk for Esotropia.

TitleRecurrent Rare Copy Number Variants Increase Risk for Esotropia.
Publication TypeJournal Article
Year of Publication2020
AuthorsWhitman, MC, Di Gioia, SAlessandro, Chan, W-M, Gelber, A, Pratt, BM, Bell, JL, Collins, TE, Knowles, JA, Armoskus, C, Pato, M, Pato, C, Shaaban, S, Staffieri, S, MacKinnon, S, Maconachie, GDE, Elder, JE, Traboulsi, EI, Gottlob, I, Mackey, DA, Hunter, DG, Engle, EC
Corporate AuthorsStrabismus Genetics Research Consortium
JournalInvest Ophthalmol Vis Sci
Date Published2020 08 03
KeywordsCase-Control Studies, DNA Copy Number Variations, Esotropia, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Infant, Male, Markov Chains, Polymerase Chain Reaction, Risk Factors

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.

Alternate JournalInvest Ophthalmol Vis Sci
PubMed ID32780866
PubMed Central IDPMC7443120
Grant ListR01 EY015298 / EY / NEI NIH HHS / United States
R01 EY016482 / EY / NEI NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
K08 EY027850 / EY / NEI NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 EY016514 / EY / NEI NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States