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Background: Variations in the protocadherin gene FAT1 have recently been associated with a syndrome that includes coloboma, facial dysmorphism, renal failure, syndactyly, and other developmental defects., Materials and Methods: Detailed medical and family history, physical examination, and molecular analysis., Results: This non-dysmorphic, intellectually normal 51-year-old woman presented with bilateral colobomata and renal failure of unclear etiology, and asymmetric sensorineural hearing loss. Family history was notable for multiple family members with various forms of cancer. Whole exome sequencing revealed a homozygous frame shift variant in FAT1 , predicted to truncate the FAT1 protein at the furthest position in the protein structure published to date in a patient with coloboma., Conclusions: This case provides further evidence of the pleiotropic effects of FAT1 in optic fissure closure and kidney function. Also, because this variant is in the last exon, it would be anticipated to escape nonsense-mediated decay, opening the possibility that the protein is made and expressed, but not completely functional, as its intracellular domain is truncated.

Purpose: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid., Methods: Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT., Results: Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina-like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure., Conclusions: These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure.

Background: Uveal colobomata are eye defects that result from failure of the optic fissure of the neuroectoderm-derived optic cup to close between weeks 5-7 of fetal life. Mutations in YAP1 have previously been linked to uveal coloboma. We present the clinical features and genetic basis of a one-year-old male with bilateral uveal colobomata., Materials and Methods: Clinical features were gathered from an age-appropriate evaluation and retrospectively from clinical records. DNA samples were collected from the proband, his uncle (who also had coloboma), both parents, and one sibling. Whole-genome sequencing of the coding regions and intron-exon boundaries confirmed a mutation in the proband. These genetic findings were verified using the Sanger method of DNA sequencing., Results: The proband is a male with congenital bilateral colobomata (iris/retina/nerve), reduced vision, nystagmus with null point, bilateral microcornea, right microphthalmia, possible mild right hemifacial microsomia, a tubular nose, possible spina bifida occulta, and astigmatism. Whole-genome sequencing confirmed a heterozygous YAP1 frameshift mutation NM_001130145.3:c.178dupG p.(Asp60GlyfsTer52) in the proband. This mutation was absent in all other tested family members., Conclusions: We report a de novo mutation in YAP1 that likely results in nonsense-mediated decay. Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband. Further insight into YAP1 mutations may have implications in the prevention/treatment of uveal coloboma and other syndromic disorders.

Uveal coloboma is a condition defined by missing ocular tissues and is a significant cause of childhood blindness. It occurs from a failure of the optic fissure to close during embryonic development and may lead to missing parts of the iris, ciliary body, retina, choroid, and optic nerve. Because there is no treatment for coloboma, efforts have focused on prevention. While several genetic causes of coloboma have been identified, little definitive research exists regarding the environmental causes of this condition. We review the current literature on environmental factors associated with coloboma in an effort to guide future research and preventative counseling related to this condition., (Copyright © 2021. Published by Elsevier Inc.)

Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high-throughput screening of 38 known coloboma-associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand-binding domain, was a missense change in the highly conserved DNA-binding domain predicted to affect the protein's DNA-binding ability. In vitro studies revealed lower steady-state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild-type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA-binding domain could result in human disease., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Typical ocular coloboma is caused by defective closure of the embryonal fissure. The occurrence of coloboma can be sporadic, hereditary (known or unknown gene defects) or associated with chromosomal abnormalities. Ocular colobomata are more often associated with systemic abnormalities when caused by chromosomal abnormalities. The ocular manifestations vary widely. At one extreme, the eye is hardly recognisable and non-functional-having been compressed by an orbital cyst, while at the other, one finds minimalistic involvement that hardly affects the structure and function of the eye. In the fundus, the variability involves the size of the coloboma (anteroposterior and transverse extent) and the involvement of the optic disc and fovea. The visual acuity is affected when coloboma involves disc and fovea, or is complicated by occurrence of retinal detachment, choroidal neovascular membrane, cataract, amblyopia due to uncorrected refractive errors, etc. While the basic birth anomaly cannot be corrected, most of the complications listed above are correctable to a great extent. Current day surgical management of coloboma-related retinal detachments has evolved to yield consistently good results. Cataract surgery in these eyes can pose a challenge due to a combination of microphthalmos and relatively hard lenses, resulting in increased risk of intra-operative complications. Prophylactic laser retinopexy to the border of choroidal coloboma appears to be an attractive option for reducing risk of coloboma-related retinal detachment. However, a majority of the eyes have the optic disc within the choroidal coloboma, thus making it difficult to safely administer a complete treatment., (© 2021. The Author(s).)

Purpose: To investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma., Design: Cross-sectional observational study., Methods: setting: Single-center ophthalmic genetics clinic. study population: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. observational procedure: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. main outcome measure: Prevalence of abnormal findings on systemic testing., Results: Uveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was ≥20/40 in 45% of eyes; 23% of eyes had BCVA of ≤20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention., Conclusions: Although some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context., (Published by Elsevier Inc.)

ARHGAP35 has known roles in cell migration, invasion and division, neuronal morphogenesis, and gene/mRNA regulation; prior studies indicate a role in cancer in humans and in the developing eyes, neural tissue, and renal structures in mice. We identified damaging variants in ARHGAP35 in five individuals from four families affected with anophthalmia, microphthalmia, coloboma and/or anterior segment dysgenesis disorders, together with variable non-ocular phenotypes in some families including renal, neurological, or cardiac anomalies. Three variants affected the extreme C-terminus of the protein, with two resulting in a frameshift and C-terminal extension and the other a missense change in the Rho-GAP domain; the fourth (nonsense) variant affected the middle of the gene and is the only allele predicted to undergo nonsense-mediated decay. This study implicates ARHGAP35 in human developmental eye phenotypes. C-terminal clustering of the identified alleles indicates a possible common mechanism for ocular disease but requires further studies., (© 2022. The Author(s).)

Purpose of Review: To integrate knowledge on the embryologic and molecular basis of optic fissure closure with clinical observations in patients with uveal coloboma., Recent Findings: Closure of the optic fissure has been well characterized and many genetic alterations have been associated with coloboma; however, molecular mechanisms leading to coloboma remain largely unknown. In the past decade, we have gained better understanding of genes critical to eye development; however, mutations in these genes have been found in few individuals with coloboma. CHD7 mutations have been identified in patients with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth, genital anomalies, and ear anomalies or deafness). Animal models are bringing us closer to a molecular understanding of optic fissure closure., Summary: Optic fissure closure requires precise orchestration in timing and apposition of two poles of the optic cup. The relative roles of genetics and environment on this process remain elusive. While most cases of coloboma are sporadic, autosomal dominant, autosomal recessive, and X-linked inheritance patterns have been described. Genetically, colobomata demonstrate pleiotropy, heterogeneity, variable expressivity, and reduced penetrance. Coloboma is a complex disorder with a variable prognosis and requires regular examination to optimize visual acuity and to monitor for potential complications.

Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.

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., (© 2020 Wiley Periodicals LLC.)