CUGC for syndromic microphthalmia including next-generation sequencing-based approaches

Eintracht, Jonathan; Cortón, Marta; FitzPatrick, David R.; Moosajee, Mariya

doi:10.1038/s41431-019-0565-4

Cited by 4 publications

(5 citation statements)

References 78 publications

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“…20–22 Although the majority of bilateral microphthalmia/anophthalmia cases are due to dominant monoallelic mutations, homozygous and compound heterozygous loss-of-function variants are found in STRA6 and RAX . 6,23,24…”

Section: How To Identify Patients Who May Benefit From Genetic Screen...mentioning

confidence: 99%

“…[20][21][22] Although the majority of bilateral microphthalmia/anophthalmia cases are due to dominant monoallelic mutations, homozygous and compound heterozygous loss-of-function variants are found in STRA6 and RAX. 6,23,24 Autosomal dominant disease. Autosomal dominant inheritance is defined by a disease or trait caused by a single heterozygous variant affecting one allele of an autosomal gene.…”

Section: How To Identify Patients Who May Benefit From Genetic Screen...mentioning

confidence: 99%

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Practical guide to genetic screening for inherited eye diseases

et al. 2020

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Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

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Section: How To Identify Patients Who May Benefit From Genetic Screen...mentioning

confidence: 99%

Section: How To Identify Patients Who May Benefit From Genetic Screen...mentioning

confidence: 99%

Practical guide to genetic screening for inherited eye diseases

et al. 2020

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“…Animal models, including the mouse, rat, zebrafish, drosophila, Xenopus , chick and dog have all contributed to our understanding of ocular development and disease (Kaukonen et al, 2018 ; Kolosova et al, 2018 ; Moore et al, 2018 ; Sghari and Gunhaga, 2018 ; Zhu et al, 2018 ; Kha et al, 2019 ; Richardson et al, 2019 ). Despite their invaluable contribution, animal models are suboptimal for critical reasons: (i) Differences in gene expression between animal models do not inform our understanding of human disease mechanisms; for example, MAB21L2 , which is required for eye morphogenesis and cell survival in the developing optic cup and lens, and is associated with microphthalmia and coloboma in humans (Gath and Gross, 2019 ; Eintracht et al, 2020 ). However, the closest expression pattern to humans is still unknown due to differing mab21l2 expression patterns and localization in the chick, mouse, and zebrafish (Sghari and Gunhaga, 2018 ; Gath and Gross, 2019 ).…”

Section: A New Tool To Study Ocular Developmentmentioning

confidence: 99%

“…The common causative genes encode EFTFs such as SOX2, PAX6, VSX2 , and OTX2 , or those that encode components of the retinoic acid signaling pathway such as STRA6 or ALDH1A3 (Williamson and FitzPatrick, 2014 ). Chromosomal abnormalities are responsible for approximately 7–15% of syndromic cases (Eintracht et al, 2020 ).…”

Section: Developmental Eye Disorders and Associated Genetic Variants mentioning

confidence: 99%

The Use of Induced Pluripotent Stem Cells as a Model for Developmental Eye Disorders

Eintracht¹,

Toms

Moosajee

2020

Front. Cell. Neurosci.

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Approximately one-third of childhood blindness is attributed to developmental eye disorders, of which 80% have a genetic cause. Eye morphogenesis is tightly regulated by a highly conserved network of transcription factors when disrupted by genetic mutations can result in severe ocular malformation. Human-induced pluripotent stem cells (hiPSCs) are an attractive tool to study early eye development as they are more physiologically relevant than animal models, can be patient-specific and their use does not elicit the ethical concerns associated with human embryonic stem cells. The generation of self-organizing hiPSC-derived optic cups is a major advancement to understanding mechanisms of ocular development and disease. Their development in vitro has been found to mirror that of the human eye and these early organoids have been used to effectively model microphthalmia caused by a VSX2 variant. hiPSC-derived optic cups, retina, and cornea organoids are powerful tools for future modeling of disease phenotypes and will enable a greater understanding of the pathophysiology of many other developmental eye disorders. These models will also provide an effective platform for identifying molecular therapeutic targets and for future clinical applications.

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“…For example, MAB21L2 is required for eye morphogenesis and cell survival in the developing optic cup and lens in humans yet mab21l2 expression patterns in the chick, mouse and zebrafish are still unknown. [5][6][7] (iii) Mature anatomy of the eye can vary between species, such as the absence of the macula in rodents and other small mammals. 8 (iv) Disease phenotypes observed in animals do not always mimic those seen in humans.…”

Section: Introductionmentioning

confidence: 99%

Efficient embryoid-based method to improve generation of optic vesicles from human induced pluripotent stem cells

et al. 2022

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Animal models have provided many insights into ocular development and disease, but they remain suboptimal for understanding human oculogenesis. Eye development requires spatiotemporal gene expression patterns and disease phenotypes can differ significantly between humans and animal models, with patient-associated mutations causing embryonic lethality reported in some animal models. The emergence of human induced pluripotent stem cell (hiPSC) technology has provided a new resource for dissecting the complex nature of early eye morphogenesis through the generation of three-dimensional (3D) cellular models. By using patient-specific hiPSCs to generate in vitro optic vesicle-like models, we can enhance the understanding of early developmental eye disorders and provide a pre-clinical platform for disease modelling and therapeutics testing. A major challenge of in vitro optic vesicle generation is the low efficiency of differentiation in 3D cultures. To address this, we adapted a previously published protocol of retinal organoid differentiation to improve embryoid body formation using a microwell plate. Established morphology, upregulated transcript levels of known early eye-field transcription factors and protein expression of standard retinal progenitor markers confirmed the optic vesicle/presumptive optic cup identity of in vitro models between day 20 and 50 of culture. This adapted protocol is relevant to researchers seeking a physiologically relevant model of early human ocular development and disease with a view to replacing animal models.

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CUGC for syndromic microphthalmia including next-generation sequencing-based approaches

Cited by 4 publications

References 78 publications

Practical guide to genetic screening for inherited eye diseases

Practical guide to genetic screening for inherited eye diseases

The Use of Induced Pluripotent Stem Cells as a Model for Developmental Eye Disorders

Efficient embryoid-based method to improve generation of optic vesicles from human induced pluripotent stem cells

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