Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

Delahaye, Andrée; Bitoun, Pierre; Drunat, Séverine; Gérard-Blanluet, Marion; Chassaing, Nicolas; Toutain, Annick; Verloes, Alain; Gatelais, Frédérique; Legendre, M.; Faivre, Laurence; Passemard, Sandrine; Aboura, Azzedine; Kaltenbach, Sophie; Quentin, Samuel; Dupont, Céline; Tabet, Anne‐Claude; Amselem, Serge; Élion, Jacques; Gressèns, Pierre; Pipiras, Eva; Benzacken, Brigitte

doi:10.1038/ejhg.2011.233

Cited by 22 publications

(16 citation statements)

References 44 publications

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“…These include aneuploidy (mainly trisomy 13 and 18), triploidy and certain microdeletion or microduplication syndromes, such as 4p-syndrome (MIM#194190) or duplication of 3q, 4p or 10q regions. The introduction of aCGH has made it possible to identify cryptic chromosomal abnormalities in 10-15% of patients with syndromic ocular involvement and normal karyotyping (Balikova et al 2011;Delahaye et al 2012). However, in non-syndromic A/M the frequency of chromosomal abnormalities identified by aCGH is low (Raca et al 2011).…”

Section: Etiologiesmentioning

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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Section: Etiologiesmentioning

confidence: 99%

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

et al. 2019

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“…Molecular karyotyping (comparative genomic hybridization array), allows identification of unbalanced chromosomal rearrangements in an additional 3 to 10% of patients depending on the presence of extraocular features. 12,13 In addition, AM phenotype can be the consequence of mutations that affect the function of genes known to play a crucial role in eye development. Since the last decade, many genes have been implicated in isolated and syndromic forms of AM phenotype and all patterns of inheritance have been reported (dominant, recessive, and X-linked transmission manner).…”

Section: Causesmentioning

confidence: 99%

Genetic Advances in Microphthalmia

2016

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Congenital ocular anomalies such as anophthalmia and microphthalmia (AM) are severe craniofacial malformations in human. The etiologies of these ocular globe anomalies are diverse but the genetic origin appears to be a predominant cause. Until recently, genetic diagnosis capability was rather limited in AM patients and only a few genes were available for routine genetic testing. While some issues remain poorly understood, knowledge regarding the molecular basis of AM dramatically improved over the last years with the development of new molecular screening technologies. Thus, the genetic cause is now identifiable in more than 50% of patients with a severe bilateral eye phenotype and in around 30% of all AM patients taken together. Such advances in the knowledge of these genetic bases are important as they improve the quality of care, in terms of diagnosis, prognosis, and genetic counseling delivered to the patients and their families.

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“…Anomalies of the head were reported in the postnatal and prenatal cases [ 3 – 5 , 7 , 11 ]. Additional features associated with microdeletion involve micro−/retrognathia, maxillary hypoplasia, cleft uvula/palate, high arch palate or Pierre Robin sequence (PRS) [ 1 – 4 , 8 , 10 – 12 ] (Table 2 ). Micro−/retrognathia was seen during the US scan in the 17th week of pregnancy and orofacial abnormality was even noticed in the first trimester ultrasound scan in our case when the PRS in the fetus was suspected.…”

Section: Discussionmentioning

confidence: 99%

“…Micrognathia, glosoptosis, and cleft palate characterize PRS. Micrognathia and cleft palate are detected in individuals with BMP4 haploinsufficiency [ 2 , 10 – 12 ] (Table 2 ). The role of BMP4 in otocephaly-agnathia has been previously implicated [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy

et al. 2017

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BackgroundInterstitial microdeletion 14q22q23 is a rare chromosomal syndrome associated with variable defects: microphthalmia/anophthalmia, pituitary anomalies, polydactyly/syndactyly of hands and feet, micrognathia/retrognathia. The reports of the microdeletion 14q22q23 detected in the prenatal stages are limited and the range of clinical features reveals a quite high variability.Case presentationWe report a detection of the microdeletion 14q22.1q23.1 spanning 7,7 Mb and involving the genes BMP4 and OTX2 in the foetus by multiplex ligation-dependent probe amplification (MLPA) and verified by microarray subsequently. The pregnancy was referred to the genetic counselling for abnormal facial profile observed in the first trimester ultrasound scan and micrognathia (suspicion of Pierre Robin sequence), hypoplasia nasal bone and polydactyly in the second trimester ultrasound scan. The pregnancy was terminated on request of the parents.ConclusionAn abnormal facial profile detected on prenatal scan can provide a clue to the presence of rare chromosomal abnormalities in the first trimester of pregnancy despite the normal result of the first trimester screening test. The patients should be provided with genetic counselling. Usage of quick and sensitive methods (MLPA, microarray) is preferable for discovering a causal aberration because some of the CNVs cannot be detected with conventional karyotyping in these cases. To the best of our knowledge, this is the earliest detection of this microdeletion (occurred de novo), the first case detected by MLPA and confirmed by microarray. Literature review of the genotype-phenotype correlation in similar reports leads us to the conclusion that dosage imbalance of the chromosomal segment 14q22q23 (especially haploinsuffiency of the genes BMP4 and OTX2) contributes significantly to orofacial abnormalities. Association of the region with the Pierre Robin sequence appears to be plausible.

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Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

Cited by 22 publications

References 44 publications

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

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

Genetic Advances in Microphthalmia

Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy

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