Recurrent Rare Copy Number Variants Increase Risk for Esotropia

Area of Science:

• Genetics
• Ophthalmology
• Genomic Medicine

Background:

• Comitant esotropia is a common form of strabismus with a complex etiology.
• The role of rare copy number variants (CNVs) in the genetic predisposition to comitant esotropia remains incompletely understood.

Purpose of the Study:

• To investigate the association between rare CNVs and the risk of developing comitant esotropia.
• To identify specific CNVs that confer increased susceptibility to comitant esotropia.

Main Methods:

• Utilized Illumina SNP genotyping and Hidden Markov Model (HMM) algorithms (PennCNV, QuantiSNP) to identify CNVs in 1614 esotropia cases and 3922 controls.
• Excluded common CNVs and focused on deletions/duplications >10 kb, performing association testing with 1 million permutations.
• Confirmed significant CNVs using digital droplet polymerase chain reaction (ddPCR) and whole genome sequencing for breakpoint analysis.

Main Results:

• Esotropia patients exhibited similar CNV rates but greater total length and average size of deletions/duplications compared to controls.
• Identified three recurrent rare duplications significantly associated with increased esotropia risk (P = 1 × 10-6).
• These duplications include chr2p11.2 (lncRNA, 2 microRNAs), chr4p15.2 (lncRNA), and chr10q11.22 (protein-coding genes, lncRNA, pseudogenes), with odds ratios ranging from 8.96 to 14.16.

Conclusions:

• Rare CNVs represent a significant source of genetic variation contributing to the polygenic risk of comitant esotropia.
• The identified recurrent duplications are strongly associated with esotropia, highlighting their role in its pathophysiology.
• Further research into the functional impact of these duplications is warranted to elucidate the mechanisms underlying esotropia development.