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It is classed as part of the clinical spectrum of structural eye malformations with microphthalmia and anophthalmia, collectively abbreviated to MAC. Despite deliberate attempts to identify causative variants in MAC, many patients remain without a genetic diagnosis. To reveal potential candidate genes, we utilised transcriptomes experimentally generated from embryonic eye tissues derived from humans, mice, zebrafish, and chicken at stages coincident with optic fissure closure. Our in-silico analyses found 10 genes with optic fissure-specific enriched expression: ALDH1A3, BMPR1B, EMX2, EPHB3, NID1, NTN1, PAX2, SMOC1, TENM3, and VAX1. In situ hybridization revealed that all 10 genes were broadly expressed ventrally in the developing eye but that only PAX2 and NTN1 were expressed in cells at the edges of the optic fissure margin. Of these conserved optic fissure genes, EMX2, NID1, and EPHB3 have not previously been associated with human MAC cases. Targeted genetic manipulation in zebrafish embryos using CRISPR\/Cas9 caused the developmental MAC phenotype for emx2 and ephb3. We analysed available whole genome sequencing datasets from MAC patients and identified a range of variants with plausible causality. In combination, our data suggest that expression of genes involved in ventral eye development is conserved across a range of vertebrate species and that EMX2, NID1, and EPHB3 are candidate loci that warrant further functional analysis in the context of MAC and should be considered for sequencing in cohorts of patients with structural eye malformations.<\/jats:p>","DOI":"10.3390\/biom13020293","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T02:57:32Z","timestamp":1675652252000},"page":"293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species"],"prefix":"10.3390","volume":"13","author":[{"given":"Violeta","family":"Trejo-Reveles","sequence":"first","affiliation":[{"name":"Roslin Institute, R(D)SVS, Easter Bush Campus, University of Edinburgh, Edinburgh EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5598-6274","authenticated-orcid":false,"given":"Nicholas","family":"Owen","sequence":"additional","affiliation":[{"name":"Development, Ageing and Disease, UCL Institute of Ophthalmology, London EC1V 9EL, UK"},{"name":"Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1A, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian Ho","family":"Ching Chan","sequence":"additional","affiliation":[{"name":"Roslin Institute, R(D)SVS, Easter Bush Campus, University of Edinburgh, Edinburgh EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Toms","sequence":"additional","affiliation":[{"name":"Development, Ageing and Disease, UCL Institute of Ophthalmology, London EC1V 9EL, UK"},{"name":"Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1A, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4964-2138","authenticated-orcid":false,"given":"Jeffrey J.","family":"Schoenebeck","sequence":"additional","affiliation":[{"name":"Roslin Institute, R(D)SVS, Easter Bush Campus, University of Edinburgh, Edinburgh EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1688-5360","authenticated-orcid":false,"given":"Mariya","family":"Moosajee","sequence":"additional","affiliation":[{"name":"Development, Ageing and Disease, UCL Institute of Ophthalmology, London EC1V 9EL, UK"},{"name":"Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1A, UK"},{"name":"Department of Genetics, Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-5100","authenticated-orcid":false,"given":"Joe","family":"Rainger","sequence":"additional","affiliation":[{"name":"Roslin Institute, R(D)SVS, Easter Bush Campus, University of Edinburgh, Edinburgh EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3109\/13816819209046487","article-title":"Epidemiology of Congenital Eye Malformations in 131,760 Consecutive Births","volume":"13","author":"Stoll","year":"1992","journal-title":"Ophthalmic Paediatr. 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