Review of evidence for environmental causes of uveal coloboma

Selzer, Evan B; Blain, Delphine; Hufnagel, Robert B.; Lupo, Philip J.; Mitchell, Laura E.; Brooks, Brian P.

doi:10.1016/j.survophthal.2021.12.008

Cited by 6 publications

(2 citation statements)

References 158 publications

(167 reference statements)

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“…Within these disorders, ocular coloboma (OC) is the most common and considered part of the clinical phenotypic spectrum, along with anophthalmia (a completely missing eye) and microphthalmia (a small, underdeveloped eye), together referred to as MAC. The developmental insults that cause MAC are mostly genetic but may also be influenced by environmental factors [4][5][6]. They occur early in gestation and typically affect the morphogenesis and structural development of the optic vesicle (anophthalmia) or eye cup (microphthalmia and coloboma) [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species

et al. 2023

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Ocular coloboma (OC) is a failure of complete optic fissure closure during embryonic development and presents as a tissue defect along the proximal–distal axis of the ventral eye. 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.

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Section: Introductionmentioning

confidence: 99%

Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species

et al. 2023

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show abstract

“…Within these disorders, ocular coloboma (OC) is the most common and considered part of the clinical phenotypic spectrum with anophthalmia (completely missing eye) and microphthalmia (small, underdeveloped eye), together referred to as MAC. The developmental insults that cause MAC are mostly genetic but may also be influenced by environmental factors [4][5][6]. They occur early in gestation and typically affect the morphogenesis and structural development of the optic vesicle (anophthalmia) or eye cup (microphthalmia and coloboma) [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel coloboma candidate genes through conserved gene expression analyses across four vertebrate species

Trejo-Reveles

Owen²,

Chan

et al. 2022

Preprint

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Ocular coloboma (OC) is a failure of complete optic fissure closure during embryonic development and presents as a tissue defect along the proximal distal axis of the ventral eye. 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 human, mouse, 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 scrutined 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 are conserved across a range of vertebrate species, and that EMX2, NID1, and EPHB3 are candidate loci that should be adopted into clinical diagnostic screens for patients with structural eye malformations.

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Epidemiology of Coloboma: Prevalence and Patterns in Texas, 1999–2014

Mitchell,

Chambers,

Agopian

et al. 2024

Birth Defects Research

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BackgroundColoboma is a rare congenital malformation in which part of the tissue that makes up the eye is missing and may cause visual impairment or blindness. Little is known about the epidemiology of this condition. Therefore, we obtained data from the Texas Birth Defects Registry on children identified with coloboma for the period 1999–2014.MethodsUsing information on all live births from the same period, prevalence ratios (PRs) for selected demographic and clinical factors were used to estimate associations using Poisson regression among cases with coloboma. Coloboma cases were divided into subgroups to explore patterns of co‐occurring defects and syndromes. All variables significant in unadjusted models (p < 0.05) were included in multivariable models to evaluate adjusted PRs (aPRs).ResultsWe identified 1587 cases with coloboma, of whom 934 (58.8%) were nonsyndromic, and 474 (29.9%) were isolated. When considering all identified cases, factors associated with significant differences in prevalence included plurality (multiple vs. singleton aPR = 1.4, 95% CI: 1.1–1.8); maternal education (college or greater vs. less than high school aPR = 0.7, 95% CI: 0.6–0.9); maternal race/ethnicity (Hispanic vs. non‐Hispanic White aPR = 0.9, 95% CI: 0.8–1.0); and maternal diabetes (yes vs. no aPR = 1.3, 95% CI: 1.0–1.6). There was a notable increase in the birth prevalence of coloboma during the study period (p‐for‐trend < 0.001). Effect estimates were similar across the different subgroups.ConclusionIn our large population, we identified several factors associated with the prevalence of coloboma. These findings may help define subgroups of women more likely to have children affected by coloboma, which could inform improved screening efforts.

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Review of evidence for environmental causes of uveal coloboma

Cited by 6 publications

References 158 publications

Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species

Identification of Novel Coloboma Candidate Genes through Conserved Gene Expression Analyses across Four Vertebrate Species

Identification of novel coloboma candidate genes through conserved gene expression analyses across four vertebrate species

Epidemiology of Coloboma: Prevalence and Patterns in Texas, 1999–2014

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