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Christèle Dubourg - One of the best experts on this subject based on the ideXlab platform.
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Disrupted hypothalamo-pituitary axis in association with reduced SHH underlies the pathogenesis of NOTCH-deficiency
Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Houda Hamdi-roze, Artem Kim, Wilfrid Carré, Hélène Guyodo, Michelle Ware, Aurélie Rizzo, Leslie Ratié, Maïlys Rupin, Sylvie Odent, Christèle DubourgAbstract:Context: In human, Sonic Hedgehog, SHH, haploinsufficiency is the predominant cause of Holoprosencephaly, a structural malformation of the forebrain midline characterised by phenotypic heterogeneity and incomplete penetrance. The NOTCH signalling pathway has recently been associated with Holoprosencephaly, in humans, but the precise mechanism involving NOTCH signalling during early brain development remains unknown.Objective: The aim of this study was to evaluate the relationship between SHH and NOTCH signalling in order to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain.Design: In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We reported results obtained from clinical diagnosis of a cohort composed of 141 Holoprosencephaly patients.Results: We demonstrated that inhibition of NOTCH signalling in chick embryos as well as in mouse embryos induces a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signalling pathways synergized to produce a malformed pituitary gland. Analysis of a large Holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways.Conclusions: These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human Holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.
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Integrated clinical and omics approach to rare diseases novel genes and oligogenic inheritance in Holoprosencephaly
Brain - A Journal of Neurology, 2019Co-Authors: Artem Kim, Clara Savary, Christèle Dubourg, Wilfrid Carré, Charlotte Mouden, Houda Hamdi-roze, Hélène Guyodo, Jérôme Le Douce, Laurent Pasquier, Elisabeth FloriAbstract:Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in Holoprosencephaly but its genetic basis remains unclear different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of Holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of Holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel Holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in Holoprosencephaly patients compared to two control populations (P < 10-9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in Holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of Holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.
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Holoprosencephaly
Orphanet Journal of Rare Diseases, 2007Co-Authors: Christèle Dubourg, Laurent Pasquier, Sylvie Odent, Claude Bendavid, Catherine Henry, Véronique DavidAbstract:Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog ( SHH ), ZIC2 , SIX3 , TGIF , PTCH , GLI2 and TDGF1 . A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH , ZIC2 , SIX3 and TGIF . Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.
Stephen L Kinsman - One of the best experts on this subject based on the ideXlab platform.
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White matter imaging in Holoprosencephaly in children.
Current opinion in neurology, 2004Co-Authors: Stephen L KinsmanAbstract:Purpose of review Holoprosencephaly is a disorder of forebrain development characterized by a failure of the brain to separate into two hemispheres during early development. It is now clear that many cases of Holoprosencephaly are caused by alterations in the genetic programmes that pattern the nervous system. Less is known about how a holoprosencephalic brain either forms or fails to form connections between various brain structures. Recent findings Abnormalities in the corpus callosum, corticospinal tract, medial lemniscus and cerebellar peduncles can be seen in Holoprosencephaly. Diffusion tensor imaging has been and will continue to be an important tool for imaging white matter in the brain, and will be reviewed here. Furthermore, recent evidence suggests that Holoprosencephaly can be associated with delays or abnormalities in myelination. The functional implications of white matter abnormalities in children with Holoprosencephaly is only beginning to be understood. Summary Modern neuroimaging has led to a better appreciation of the variability seen in Holoprosencephaly, an anomaly known to have multiple etiologies. Recent reviews of the biology of Holoprosencephaly identify the condition as a defect in dorsoventral patterning. More detailed white and grey matter structure-function studies are likely to shed light on how a brain with drastically altered composition and connectivity does or does not organize itself to accomplish increasingly complex developmental functions.
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Holoprosencephaly in children diffusion tensor mr imaging of white matter tracts of the brainstem initial experience
Radiology, 2002Co-Authors: Sait Albayram, Elias R Melhem, Susumu Mori, James S Zinreich, James A Barkovich, Stephen L KinsmanAbstract:PURPOSE: To evaluate the dimensions of specific white matter tracts in the brainstems (region of brain thought to be least affected) of children with Holoprosencephaly by using diffusion tensor magnetic resonance (MR) imaging and to correlate these abnormalities with forebrain malformation severity and neurologic deficit severity. MATERIALS AND METHODS: Thirteen patients with Holoprosencephaly underwent diffusion tensor MR imaging, with which white matter color maps were generated. Type of Holoprosencephaly was correlated with presence or absence of specific brainstem white matter tracts. Furthermore, patient rank based on cortico-ponto-spinal tract (CPST) and middle cerebellar peduncle (MCP) dimensions was correlated with Holoprosencephaly type and neurodevelopmental score by using Spearman rank correlation analysis. RESULTS: Two patients had alobar Holoprosencephaly, five had the semilobar type, one had the lobar type, and one had the middle-hemisphere-variant type. Four patients were excluded from anal...
Anna Verdonck - One of the best experts on this subject based on the ideXlab platform.
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genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome
American Journal of Medical Genetics Part A, 2015Co-Authors: Simon Poelmans, Tatsuro Kawamoto, Francesca Cristofoli, Constantinus Politis, Joris Vermeesch, Isabelle Bailleulforestier, Greet Hens, Koenraad Devriendt, Anna VerdonckAbstract:Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the Holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of Holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known Holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known Holoprosencephaly spectrum. © 2015 Wiley Periodicals, Inc.
Maximilian Muenke - One of the best experts on this subject based on the ideXlab platform.
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identifying environmental risk factors and gene environment interactions in Holoprosencephaly
Birth defects research, 2020Co-Authors: Yonit A Addissie, Maximilian Muenke, Angela Troia, Zoe C Wong, Joshua L Everson, Beth A Kozel, Robert J Lipinski, Kristen Malecki, Paul KruszkaAbstract:BACKGROUND Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with Holoprosencephaly risk, severity, and gene-environment interactions. METHODS For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with Holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of Holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers. RESULTS Difference in odds of exposures between cases and controls as well as within cases with varying Holoprosencephaly severity were studied. Cases included children born with Holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with Holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03). CONCLUSION The study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of Holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.
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a ccr4 not transcription complex subunit 1 cnot1 variant associated with Holoprosencephaly
American Journal of Human Genetics, 2019Co-Authors: Paul Kruszka, Joshua L Everson, Robert J Lipinski, Seth I. Berger, Karin Weiss, Ariel F. Martinez, Sungkook Hong, Kwame Anyaneyeboa, Maximilian MuenkeAbstract:Holoprosencephaly is the incomplete separation of the forebrain during embryogenesis. Both genetic and environmental etiologies have been determined for Holoprosencephaly; however, a genetic etiology is not found in most cases. In this report, we present two unrelated individuals with semilobar Holoprosencephaly who have the identical de novo missense variant in the gene CCR4-NOT transcription complex, subunit 1 (CNOT1). The variant (c.1603C>T [p.Arg535Cys]) is predicted to be deleterious and is not present in public databases. CNOT1 has not been previously associated with Holoprosencephaly or other brain malformations. In situ hybridization analyses of mouse embryos show that Cnot1 is expressed in the prosencephalic neural folds at gestational day 8.25 during the critical period for subsequent forebrain division. Combining human and mouse data, we show that CNOT1 is associated with incomplete forebrain division.
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high intellectual function in individuals with mutation positive microform Holoprosencephaly
Molecular Syndromology, 2012Co-Authors: B D Solomon, Daniel E Pinedaalvarez, Andrea L Gropman, Mary Willis, Donald W Hadley, Maximilian MuenkeAbstract:Holoprosencephaly is the most common malformation of the forebrain and typically results in severe neurocognitive impairment with accompanying midline facial anomalies. Holoprosencephaly is heterogeneous and may be caused by chromosome aberrations or environmental factors, occur in the context of a syndrome or be due to heterozygous mutations in over 10 identified genes. The presence of these mutations may result in an extremely wide spectrum of severity, ranging from brain malformations incompatible with life to individuals with normal brain findings and subtle midline facial differences. Typically, clinicians regard intellectual disability as a sign that a parent or relative of a severely affected patient may be a mildly affected mutation ‘carrier’ with what is termed microform Holoprosencephaly. Here we present 5 patients with clear phenotypic signs of microform Holoprosencephaly, all of whom have evidence of above-average intellectual function. In 4 of these 5 individuals, the molecular cause of Holoprosencephaly has been identified and includes mutations affecting SHH, SIX3, GLI2, and FGF8. This report expands the phenotypic spectrum of Holoprosencephaly and is important in the counseling of patient and affected families.
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a novel six3 mutation segregates with Holoprosencephaly in a large family
American Journal of Medical Genetics Part A, 2009Co-Authors: Benjamin D Solomon, William B. Dobyns, Felicitas Lacbawan, Mahim Jain, Sabina Domene, Erich Roessler, Cynthia A Moore, Maximilian MuenkeAbstract:Holoprosencephaly is the most common structural malformation of the forebrain in humans and has a complex etiology including chromosomal aberrations, single gene mutations and environmental components. Here we present the pertinent clinical findings among members of an unusually large kindred ascertained over 15 years ago following the evaluation and subsequent genetic work-up of a female infant with congenital anomalies. A genome-wide scan and linkage analysis showed only suggestive evidence of linkage to markers on chromosome 2 among the most likely of several pedigree interpretations. We now report that a novel missense mutation in the SIX3 Holoprosencephaly gene is the likely cause in this family. Molecular genetic analysis and/or clinical characterization now show that at least 15 members of this family are presumed SIX3 mutation gene carriers, with clinical manifestations ranging from phenotypically normal adults (non-penetrance) to alobar Holoprosencephaly incompatible with postnatal life. This particular family represents a seminal example of the variable manifestations of gene mutations in Holoprosencephaly and difficulties encountered in their elucidation.
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Mutations in Holoprosencephaly.
Human mutation, 2000Co-Authors: Deeann Wallis, Maximilian MuenkeAbstract:Holoprosencephaly (HPE) is the most common developmental defect of the forebrain and midface in humans. In Holoprosencephaly the cerebral hemispheres of the brain fail to separate into distinct left and right hemispheres. This malformation is due to the improper specification and formation of the forebrain during early development. When one considers the great number and kinds of genetic interactions that must occur to properly pattern the developing forebrain, it is not surprising that HPE is extremely heterogeneous. In addition to teratogenic agents, several genes are implicated as the cause of HPE. At least 12 different loci have been associated with HPE and now several distinct human genes for Holoprosencephaly have been identified. These genes include Sonic Hedgehog (SHH), ZIC2, SIX3, and TG-interacting factor (TGIF). Here we present an overview of the presently known genes causing human Holoprosencephaly. We discuss their functional role in development of the forebrain and summarize the mutations and polymorphisms that have been identified within them. Hum Mutat 16:99-108, 2000. Published 2000 Wiley-Liss, Inc.
Lucilene Arilho Ribeiro - One of the best experts on this subject based on the ideXlab platform.
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single maxillary central incisor Holoprosencephaly and Holoprosencephaly like phenotype
American Journal of Medical Genetics Part A, 2006Co-Authors: Antonio Richiericosta, Lucilene Arilho RibeiroAbstract:Three patients-one with alobar Holoprosencephaly and two with a Holoprosencephaly-like phenotype-are reported with no identifiable mutations. In each case, one parent had a single maxillary central incisor (SMCI). We briefly review the Holoprosencephaly-like phenotype and present a table of 25 conditions with SMCI.
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PTCH mutations in four Brazilian patients with Holoprosencephaly and in one with Holoprosencephaly-like features and normal MRI.
American journal of medical genetics. Part A, 2006Co-Authors: Lucilene Arilho Ribeiro, Jeffrey C. Murray, Antonio Richieri-costaAbstract:We report five Brazilian probands with PATCHED (PTCH) mutations and highly variable phenotypes with Holoprosencephaly in four cases and Holoprosencephaly-like facial features with a normal MRI in a fifth case. Three of our mutations were novel: Ala443Gly, Val751Gly, and Val908Gly. Two patients had the same mutation (Val908Gly), but were phenotypically different: alobar Holoprosencephaly, absent nasal septum, and midline cleft lip-palate in one case, and lobar Holoprosencephaly, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other. One of our patients had a Thr1052Met mutation, Holoprosencephaly-like facial features, and a normal MRI. Ming et al. [(2002); Hum Genet 110:297-301] reported an identical mutation, but with alobar Holoprosencephaly.
