Identification of 4 novel human ocular coloboma genes ANK3, BMPR1B, PDGFRA, and CDH4 through evolutionary conserved vertebrate gene analysis

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• Ocular coloboma is a congenital eye disorder resulting from failed optic fissure fusion.
• Genetic and environmental factors contribute to ocular coloboma, with a high percentage of patients remaining undiagnosed.
• Understanding the genetic basis of ocular coloboma is crucial for diagnosis and treatment.

Purpose of the Study:

• Identify novel causative genes for ocular coloboma using cross-species comparative meta-analysis.
• Improve molecular diagnostic yield for patients with undiagnosed ocular coloboma.
• Elucidate the genetic mechanisms underlying optic fissure morphogenesis.

Main Methods:

• In silico analysis to identify evolutionarily conserved differentially expressed genes.
• In situ hybridization and gene knockdown/rescue experiments in zebrafish to validate gene function and expression.
• Analysis of the 100,000 Genomes Project for pathogenic variants in candidate genes.

Main Results:

• Nine conserved differentially expressed genes between zebrafish and mouse were identified.
• Expression patterns of zebrafish ank3a, bmpr1ba/b, cdh4, and pdgfaa localized to critical ocular development regions.
• Knockdown of ank3, bmpr1b, and pdgfaa induced coloboma and/or microphthalmia phenotypes.
• Novel pathogenic variants in ANK3, BMPR1B, PDGFRA, and CDH4 were found in 8 unrelated families.
• BMPR1B rescue experiments provided evidence of variant pathogenicity.

Conclusions:

• Cross-species meta-analysis is effective for discovering novel ocular coloboma genes.
• This approach can increase diagnostic yield for unsolved cases.
• Findings contribute to understanding the genetic basis of optic fissure development.