Mutational Screening of<i>FOXE3, GDF3, ATOH7</i>, and<i>ALDH1A3</i>in Congenital Ocular Malformations. Possible Contribution of the FOXE3 p.VAL201MET Variant to the Risk of Severe Eye Malformations

García-Montalvo, Iván Antonio; Pelcastre-Luna, E.; Nelson-Mora, Janikua; Buentello-Volante, Beatríz; Miranda‐Duarte, Antonio; Zenteno, Juan Carlos

doi:10.3109/13816810.2014.903983

Cited by 14 publications

(10 citation statements)

References 9 publications

(8 reference statements)

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“…No nonsense or frameshift mutations in GDF3 have been published in association with eye defects. 20 Incomplete penetrance was also present in our family and in a family with a different mutation in the GDF3 gene, c.914T > C, predicting p.Leu305Pro, in which two individuals carried this missense substitution, but only one individual manifested unilateral microphthalmia. 7 To explain the non-penetrance, it has been hypothesized that sequence variations in different BMP ligands can contribute additively to the ocular or skeletal phenotypes.…”

Section: Discussionsupporting

confidence: 51%

“…In studies of MAC in which GDF3 was sequenced, five missense sequence variants found in a cohort of 472 patients accounted for 1.7% of individuals screened 19 and GDF3 variants thus remain rare as putative causes of MAC. 20 Three of the above amino acid substitutions in GDF3 were predicted to be benign or a polymorphism by at least one software prediction program ( Table 1 ); all of the published missense variants have been detected in control databases, with two (c.820C > T, predicting p.Arg274Trp, and c.914T > C, predicting p.Leu305Pro) being present in a homozygous state in these databases ( Table 1 ). No nonsense or frameshift mutations in GDF3 have been published in association with eye defects.…”

Section: Discussionmentioning

confidence: 99%

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A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 ( GDF3 ) in a female with unilateral anophthalmia and skeletal anomalies

Bardakjian

Krall

et al. 2017

American Journal of Ophthalmology Case Reports

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PurposeThe genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 (GDF3) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies.ObservationsExome sequencing revealed that the proposita was heterozygous for c.796C > T, predicting p.Arg266Cys, in GDF3. Sanger sequencing confirmed the mutation and showed that the unaffected mother was heterozygous for the same missense substitution.Conclusions and importanceAlthough transfection studies with the p.Arg266Cys mutation have shown that this amino acid substitution is likely to impair function, non-penetrance for the ocular defects was apparent in this family and has been observed in other families with sequence variants in GDF3. We conclude p.Arg266Cys and other GDF3 mutations can be non-penetrant, making pathogenicity more difficult to establish when sequence variants in this gene are present in patients with structural eye defects.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 ( GDF3 ) in a female with unilateral anophthalmia and skeletal anomalies

Bardakjian

Krall

et al. 2017

American Journal of Ophthalmology Case Reports

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“…FOXE3 is known to be one of the PAX6 master gene targets (Dimanlig et al 2001) and recently, demonstrated that its function is mediated via transcriptional regulation of DNAJB1, which is vital for development of the lens and the maintenance of its transparency. We and others have shown that truncating and missense FOXE3 mutations are involved in a recessive phenotype of primary congenital aphakia, microphthalmia and sclerocornea (Ali et al 2010;Anjum et al 2010;Chassaing et al 2014;Garcia-Montalvo et al 2014;Iseri et al 2009;Islam et al 2015;Jimenez et al 2011;Pantoja-Melendez et al 2013;Plaisancie et al 2018a;Reis et al 2010;Saboo et al 2017;Ullah et al 2016;Valleix et al 2006).…”

Section: Foxe3 (Forkhead Box E3)mentioning

confidence: 99%

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

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“…The finding was supported by two genome-wide association studies, which identified SNP (rs3858145, p=3.4×10 −10 ) and SNP (rs1900004, p=2.67×10 −33 ) within 20 kb and 10 kb of ATOH7 , respectively 58 59. However, pathogenic ATOH7 variants were not discovered in an investigation of 34 patients with ONH60 and 76 other patients with microphthalmia/anophthalmia/coloboma 61. Homozygous knockout Atoh7 −/− mice are viable and fertile, and appear normal externally.…”

Section: Introductionmentioning

confidence: 99%

Genetic causes of optic nerve hypoplasia

Yin

Lewis

2017

J Med Genet

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Optic nerve hypoplasia (ONH) is the most common congenital optic nerve anomaly and a leading cause of blindness in the USA. Although most cases of ONH occur as isolated cases within their respective families, the advancement in molecular diagnostic technology has made us realise that a substantial fraction of cases has identifiable genetic causes, typically de novo mutations. An increasing number of genes has been reported, mutations of which can cause ONH. Many of the genes involved serve as transcription factors, participating in an intricate multistep process critical to eye development and neurogenesis in the neural retina. This review will discuss the respective genes and mutations, human phenotypes, and animal models that have been created to gain a deeper understanding of the disorders. The identification of the underlying gene and mutation provides an important step in diagnosis, medical care and counselling for the affected individuals and their families. We envision that future research will lead to further disease gene identification, but will also teach us about gene-gene and gene-environment interactions relevant to optic nerve development. How much of the functional impairment of the various forms of ONH is a reflection of altered morphogenesis versus neuronal homeostasis will determine the prospect of therapeutic intervention, with the ultimate goal of improving the quality of life of the individuals affected with ONH.

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Mutational Screening ofFOXE3, GDF3, ATOH7, andALDH1A3in Congenital Ocular Malformations. Possible Contribution of the FOXE3 p.VAL201MET Variant to the Risk of Severe Eye Malformations

Cited by 14 publications

References 9 publications

A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 ( GDF3 ) in a female with unilateral anophthalmia and skeletal anomalies

A recurrent, non-penetrant sequence variant, p.Arg266Cys in Growth/Differentiation Factor 3 ( GDF3 ) in a female with unilateral anophthalmia and skeletal anomalies

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Genetic causes of optic nerve hypoplasia

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