Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Abstract

Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2-19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.

Closing the Gap: Mechanisms of Epithelial Fusion During Optic Fissure Closure

“…MAC can affect either one or both eyes, can vary asymmetrically in severity, and can occur either in isolation, with other ocular features such as anterior segment dysgenesis (ASD) or cataract (complex) or as part of a wider developmental syndrome (Williamson and FitzPatrick, 2014;Patel and Sowden, 2017). Although non-genetic causes of OC have some basis in epidemiological evidence, the disorder is considered to be largely genetic (Morrison et al, 2002;Gregory-Evans et al, 2004), with over 40 genes so far identified harboring causative mutations in OC patients (for thorough reviews of the genes implicated in human colobomas-see Patel and Sowden, 2017;ALSomiry et al, 2019;George et al, 2020;Yoon et al, 2020).…”

Neuroimaging in Children with Ophthalmological Complaints: A Review

“…Ocular coloboma is a congenital malformation that results from failure of the embryonic or choroidal fissure to close during fetal development. It is characterized by a defect or a gap in the globe and is often associated with microphthalmia 6,42–44 . The appearance of ocular colobomas may be quite variable, largely depending on when in development the fissure failed to close.…”

Analysis of BMP3 Variants In The Causality of Ocular Coloboma

“…Although coloboma can be caused by changes to environmental factors during gestation, it is primarily caused by mutations in genes necessary for ocular development (Williamson and FitzPatrick 2014;ALSomiry et al 2019;Patel and Sowden 2019;Yoon et al 2020). To date, more than 40 colobomacausing loci have been identi ed (ALSomiry et al 2019;Yoon et al 2020). These genes have well characterized roles in critical developmental processes essential to choroid ssure closure, including axial patterning of the optic cup (proximal-distal, nasal-temporal and dorsal-ventral), cell movement and shape changes, cell adhesion, extracellular matrix remodeling, and apoptosis (ALSomiry et al 2019;Yoon et al 2020).…”