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Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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2
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Toms M, Heppell C, Owen N, Malka S, Moosajee M. A Novel De Novo Missense Variant in Netrin-1 (NTN1) Associated With Chorioretinal Coloboma, Sensorineural Hearing Loss and Polydactyly. Clin Genet 2025; 107:292-299. [PMID: 39648562 PMCID: PMC11790524 DOI: 10.1111/cge.14651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/07/2024] [Accepted: 11/10/2024] [Indexed: 12/10/2024]
Abstract
Microphthalmia, anophthalmia and coloboma (MAC) comprise a highly heterogeneous spectrum of congenital ocular malformations with an estimated incidence of 1 in 5000 to 1 in 30 000 live births. Although there is likely to be a genetic component in the majority of cases, many remain without a molecular diagnosis. Netrin-1 was previously identified as a mediator of optic fissure closure from transcriptome analyses of chick and zebrafish and was shown to cause ocular coloboma when knocked out in both mouse and zebrafish. Here, we report the first patient with chorioretinal coloboma and microphthalmia harbouring a novel heterozygous likely pathogenic NTN1 missense variant, c.1483T>A p.(Tyr495Asn), validating a conserved gene function in ocular development. In addition, the patient displayed bilateral sensorineural hearing loss which was investigated by examining the sensory hair cells of ntn1a morphant zebrafish, suggesting a role for netrin-1 in hair cell development.
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Affiliation(s)
- Maria Toms
- Development, Ageing and DiseaseUCL Institute of OphthalmologyLondonUK
- The Francis Crick InstituteLondonUK
| | - Cara Heppell
- Department of GeneticsMoorfields Eye Hospital NHS Foundation TrustLondonUK
| | - Nicholas Owen
- Development, Ageing and DiseaseUCL Institute of OphthalmologyLondonUK
| | - Samantha Malka
- Department of GeneticsMoorfields Eye Hospital NHS Foundation TrustLondonUK
| | - Mariya Moosajee
- Development, Ageing and DiseaseUCL Institute of OphthalmologyLondonUK
- The Francis Crick InstituteLondonUK
- Department of GeneticsMoorfields Eye Hospital NHS Foundation TrustLondonUK
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3
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Dong S, Zou T, Zhen F, Wang T, Zhou Y, Wu J, Nagata T, Matsushita I, Gong B, Kondo H, Li Q, Zhang H. Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome. Eur J Hum Genet 2024; 32:413-420. [PMID: 38052906 PMCID: PMC10999424 DOI: 10.1038/s41431-023-01503-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 09/24/2023] [Accepted: 11/16/2023] [Indexed: 12/07/2023] Open
Abstract
Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.
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Affiliation(s)
- Shuqian Dong
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China
| | - Tongdan Zou
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Fangyuan Zhen
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China
| | - Ting Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yongwei Zhou
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China
| | - Jiahui Wu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China
| | - Tatsuo Nagata
- Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Itsuka Matsushita
- Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Bo Gong
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Hiroyuki Kondo
- Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Qiuming Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China.
| | - Houbin Zhang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
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4
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Jackson D, Moosajee M. The Genetic Determinants of Axial Length: From Microphthalmia to High Myopia in Childhood. Annu Rev Genomics Hum Genet 2023; 24:177-202. [PMID: 37624667 DOI: 10.1146/annurev-genom-102722-090617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2023]
Abstract
The axial length of the eye is critical for normal visual function by enabling light to precisely focus on the retina. The mean axial length of the adult human eye is 23.5 mm, but the molecular mechanisms regulating ocular axial length remain poorly understood. Underdevelopment can lead to microphthalmia (defined as a small eye with an axial length of less than 19 mm at 1 year of age or less than 21 mm in adulthood) within the first trimester of pregnancy. However, continued overgrowth can lead to axial high myopia (an enlarged eye with an axial length of 26.5 mm or more) at any age. Both conditions show high genetic and phenotypic heterogeneity associated with significant visual morbidity worldwide. More than 90 genes can contribute to microphthalmia, and several hundred genes are associated with myopia, yet diagnostic yields are low. Crucially, the genetic pathways underpinning the specification of eye size are only now being discovered, with evidence suggesting that shared molecular pathways regulate under- or overgrowth of the eye. Improving our mechanistic understanding of axial length determination will help better inform us of genotype-phenotype correlations in both microphthalmia and myopia, dissect gene-environment interactions in myopia, and develop postnatal therapies that may influence overall eye growth.
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Affiliation(s)
- Daniel Jackson
- Institute of Ophthalmology, University College London, London, United Kingdom;
| | - Mariya Moosajee
- Institute of Ophthalmology, University College London, London, United Kingdom;
- The Francis Crick Institute, London, United Kingdom
- Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
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Arthur P, Muok L, Nathani A, Zeng EZ, Sun L, Li Y, Singh M. Bioengineering Human Pluripotent Stem Cell-Derived Retinal Organoids and Optic Vesicle-Containing Brain Organoids for Ocular Diseases. Cells 2022; 11:3429. [PMID: 36359825 PMCID: PMC9653705 DOI: 10.3390/cells11213429] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 08/24/2023] Open
Abstract
Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina's spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized.
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Affiliation(s)
- Peggy Arthur
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Laureana Muok
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Eric Z. Zeng
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Li Sun
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
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Suzuki M, Tomita M. Genetic Variations of Vitamin A-Absorption and Storage-Related Genes, and Their Potential Contribution to Vitamin A Deficiency Risks Among Different Ethnic Groups. Front Nutr 2022; 9:861619. [PMID: 35571879 PMCID: PMC9096837 DOI: 10.3389/fnut.2022.861619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/23/2022] [Indexed: 12/01/2022] Open
Abstract
Vitamin A, an essential fat-soluble micronutrient, plays a critical role in the body, by regulating vision, immune responses, and normal development, for instance. Vitamin A deficiency (VAD) is a major cause of xerophthalmia and increases the risk of death from infectious diseases. It is also emerging that prenatal exposure to VAD is associated with disease risks later in life. The overall prevalence of VAD has significantly declined over recent decades; however, the rate of VAD is still high in many low- and mid-income countries and even in high-income countries among specific ethnic/race groups. While VAD occurs when dietary intake is insufficient to meet demands, establishing a strong association between food insecurity and VAD, and vitamin A supplementation is the primary solution to treat VAD, genetic contributions have also been reported to effect serum vitamin A levels. In this review, we discuss genetic variations associated with vitamin A status and vitamin A bioactivity-associated genes, specifically those linked to uptake of the vitamin in the small intestine and its storage in the liver, as well as their potential contribution to vitamin A deficiency risks among different ethnic groups.
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Affiliation(s)
- Masako Suzuki
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States
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Harding P, Cunha DL, Moosajee M. Animal and cellular models of microphthalmia. THERAPEUTIC ADVANCES IN RARE DISEASE 2021; 2:2633004021997447. [PMID: 37181112 PMCID: PMC10032472 DOI: 10.1177/2633004021997447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/02/2021] [Indexed: 05/16/2023]
Abstract
Microphthalmia is a rare developmental eye disorder affecting 1 in 7000 births. It is defined as a small (axial length ⩾2 standard deviations below the age-adjusted mean) underdeveloped eye, caused by disruption of ocular development through genetic or environmental factors in the first trimester of pregnancy. Clinical phenotypic heterogeneity exists amongst patients with varying levels of severity, and associated ocular and systemic features. Up to 11% of blind children are reported to have microphthalmia, yet currently no treatments are available. By identifying the aetiology of microphthalmia and understanding how the mechanisms of eye development are disrupted, we can gain a better understanding of the pathogenesis. Animal models, mainly mouse, zebrafish and Xenopus, have provided extensive information on the genetic regulation of oculogenesis, and how perturbation of these pathways leads to microphthalmia. However, differences exist between species, hence cellular models, such as patient-derived induced pluripotent stem cell (iPSC) optic vesicles, are now being used to provide greater insights into the human disease process. Progress in 3D cellular modelling techniques has enhanced the ability of researchers to study interactions of different cell types during eye development. Through improved molecular knowledge of microphthalmia, preventative or postnatal therapies may be developed, together with establishing genotype-phenotype correlations in order to provide patients with the appropriate prognosis, multidisciplinary care and informed genetic counselling. This review summarises some key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future. Plain language summary Animal and Cellular Models of the Eye Disorder, Microphthalmia (Small Eye) Microphthalmia, meaning a small, underdeveloped eye, is a rare disorder that children are born with. Genetic changes or variations in the environment during the first 3 months of pregnancy can disrupt early development of the eye, resulting in microphthalmia. Up to 11% of blind children have microphthalmia, yet currently no treatments are available. By understanding the genes necessary for eye development, we can determine how disruption by genetic changes or environmental factors can cause this condition. This helps us understand why microphthalmia occurs, and ensure patients are provided with the appropriate clinical care and genetic counselling advice. Additionally, by understanding the causes of microphthalmia, researchers can develop treatments to prevent or reduce the severity of this condition. Animal models, particularly mice, zebrafish and frogs, which can also develop small eyes due to the same genetic/environmental changes, have helped us understand the genes which are important for eye development and can cause birth eye defects when disrupted. Studying a patient's own cells grown in the laboratory can further help researchers understand how changes in genes affect their function. Both animal and cellular models can be used to develop and test new drugs, which could provide treatment options for patients living with microphthalmia. This review summarises the key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future.
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Affiliation(s)
| | | | - Mariya Moosajee
- UCL Institute of Ophthalmology, 11-43 Bath
Street, London, EC1V 9EL, UK
- Moorfields Eye Hospital NHS Foundation Trust,
London, UK
- Great Ormond Street Hospital for Children NHS
Foundation Trust, London, UK
- The Francis Crick Institute, London, UK
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Jackson D, Malka S, Harding P, Palma J, Dunbar H, Moosajee M. Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2020; 184:578-589. [PMID: 32830442 PMCID: PMC8432170 DOI: 10.1002/ajmg.c.31837] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/30/2020] [Accepted: 08/05/2020] [Indexed: 12/14/2022]
Abstract
Overall, approximately one‐quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype–phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.
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Affiliation(s)
- Daniel Jackson
- Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Samantha Malka
- Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | | | - Juliana Palma
- Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Hannah Dunbar
- Moorfields Eye Hospital NHS Foundation Trust, London, UK.,UCL Institute of Ophthalmology, London, UK
| | - Mariya Moosajee
- Moorfields Eye Hospital NHS Foundation Trust, London, UK.,UCL Institute of Ophthalmology, London, UK.,Great Ormond Street Hospital for Children NHS Trust, London, UK.,The Francis Crick Institute, London, UK
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Harding P, Brooks BP, FitzPatrick D, Moosajee M. Anophthalmia including next-generation sequencing-based approaches. Eur J Hum Genet 2020; 28:388-398. [PMID: 31358957 PMCID: PMC7029013 DOI: 10.1038/s41431-019-0479-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 06/06/2019] [Accepted: 07/16/2019] [Indexed: 11/09/2022] Open
Abstract
Name of the disease (synonyms) See Table 1, Column 1-"Name of disease" and Column 2-"Alternative names". OMIM# of the disease See Table 1, Column 3-"OMIM# of the disease". Name of the analysed genes or DNA/chromosome segments and OMIM# of the gene(s) Core genes (irrespective of being tested by Sanger sequencing or next-generation sequencing): See Table 1, Column 4-"Cytogenetic location", Column 5-"Associated gene(s)" and Column 6-"OMIM# of associated gene(s)". Additional genes (if tested by next-generation sequencing, including Whole exome/genome sequencing and panel sequencing): See Table 2, Column 1-"Gene", Column 2-"Alternative names", Column 3-"OMIM# of gene" and Column 4-"Cytogenetic location". Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the gene(s) in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
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Affiliation(s)
| | - Brian P Brooks
- Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, MD, USA
| | | | - Mariya Moosajee
- UCL Institute of Ophthalmology, London, UK. .,Moorfields Eye Hospital NHS Foundation Trust, London, UK. .,Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
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Harding P, Moosajee M. The Molecular Basis of Human Anophthalmia and Microphthalmia. J Dev Biol 2019; 7:jdb7030016. [PMID: 31416264 PMCID: PMC6787759 DOI: 10.3390/jdb7030016] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/08/2019] [Accepted: 08/08/2019] [Indexed: 12/16/2022] Open
Abstract
Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies.
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Affiliation(s)
| | - Mariya Moosajee
- UCL Institute of Ophthalmology, London EC1V 9EL, UK.
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.
- Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
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11
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Matías-Pérez D, García-Montaño LA, Cruz-Aguilar M, García-Montalvo IA, Nava-Valdéz J, Barragán-Arevalo T, Villanueva-Mendoza C, Villarroel CE, Guadarrama-Vallejo C, la Cruz RVD, Chacón-Camacho O, Zenteno JC. Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing. J Hum Genet 2018; 63:1169-1180. [PMID: 30181649 DOI: 10.1038/s10038-018-0504-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/21/2018] [Accepted: 08/03/2018] [Indexed: 01/01/2023]
Abstract
Severe congenital eye malformations, particularly microphthalmia and anophthalmia, are one of the main causes of visual handicap worldwide. They can arise from multifactorial, chromosomal, or monogenic factors and can be associated with extensive clinical variability. Genetic analysis of individuals with these defects has allowed the recognition of dozens of genes whose mutations lead to disruption of normal ocular embryonic development. Recent application of next generation sequencing (NGS) techniques for genetic screening of patients with congenital eye defects has greatly improved the recognition of monogenic cases. In this study, we applied clinical exome NGS to a group of 14 Mexican patients (including 7 familial and 7 sporadic cases) with microphthalmia and/or anophthalmia. Causal or likely causal pathogenic variants were demonstrated in ~60% (8 out of 14 patients) individuals. Seven out of 8 different identified mutations occurred in well-known microphthalmia/anophthalmia genes (OTX2, VSX2, MFRP, VSX1) or in genes associated with syndromes that include ocular defects (CHD7, COL4A1) (including two instances of CHD7 pathogenic variants). A single pathogenic variant was identified in PIEZO2, a gene that was not previously associated with isolated ocular defects. NGS efficiently identified the genetic etiology of microphthalmia/anophthalmia in ~60% of cases included in this cohort, the first from Mexican origin analyzed to date. The molecular defects identified through clinical exome sequencing in this study expands the phenotypic spectra of CHD7-associated disorders and implicate PIEZO2 as a candidate gene for major eye developmental defects.
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Affiliation(s)
| | - Leopoldo A García-Montaño
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Marisa Cruz-Aguilar
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | | | - Jessica Nava-Valdéz
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Tania Barragán-Arevalo
- Department of Human Genetics, National Institute of Pediatrics of Mexico, Mexico City, Mexico
| | - Cristina Villanueva-Mendoza
- Department of Genetics, Hospital "Dr. Luis Sanchez Bulnes", Asociación Para Evitar la Ceguera en México, Mexico City, Mexico
| | - Camilo E Villarroel
- Department of Human Genetics, National Institute of Pediatrics of Mexico, Mexico City, Mexico
| | - Clavel Guadarrama-Vallejo
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Rocío Villafuerte-de la Cruz
- Ciencias Basicas, Escuela de Medicina, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, NL, Mexico
| | - Oscar Chacón-Camacho
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Juan C Zenteno
- Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico. .,Department of Biochemistry, Faculty of Medicine, UNAM, Mexico City, Mexico.
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Bovolenta P, Martinez-Morales JR. Genetics of congenital eye malformations: insights from chick experimental embryology. Hum Genet 2018; 138:1001-1006. [PMID: 29980841 DOI: 10.1007/s00439-018-1900-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/26/2018] [Indexed: 12/27/2022]
Abstract
Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases.
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Affiliation(s)
- Paola Bovolenta
- Centro de Biología Molecular "Severo Ochoa," (CSIC/UAM), 28049, Madrid, Spain.
- CIBERER, ISCIII, 28049, Madrid, Spain.
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