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8 results on '"Philippine Garret"'

1. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network

Author

Robert Olaso, Adeline Prost, Anne-Sophie Denommé-Pichon, Magali Gorce, Anne Boland, Mélanie Fradin, Magalie Barth, Mathilde Nizon, Antonio Vitobello, Dominique Bonneau, Bertrand Isidor, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Victor Couturier, Caroline Racine, Céline Besse, Marie Vincent, Bertrand Fin, Yline Capri, Alban Ziegler, Ange-Line Bruel, Yannis Duffourd, Christophe Philippe, P. Callier, Sébastien Moutton, Aurore Garde, Médéric Jeanne, Annick Toutain, Sophie Nambot, Delphine Bacq-Daian, Charlotte Poë, Emilie Tisserant, Aurélien Juven, Julien Van-Gils, Tiffany Busa, Laurent Pasquier, Sabine Sigaudy, Arthur Sorlin, Thibaud Jouan, Philippine Garret, Corinne Chantegret, Julian Delanne, Cyril Flamant, Alinoë Lavillaureix, Clement Prouteau, Paul Rollier, Laurence Faivre, and Jean-François Deleuze

Subjects
Protocol (science), Hospital network, medicine.medical_specialty, business.industry, Infant, Newborn, Infant, Pilot Projects, Context (language use), Disease, Hospitals, Article, Intensive Care Units, Intensive care, Genetics, medicine, Etiology, Feasibility Studies, Humans, Prospective Studies, Duration (project management), Child, Intensive care medicine, business, Genetics (clinical), Blood sampling
Abstract

Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.

Published
2021

2. Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

Author

Philippine Garret, Sana Mahmoudi, Blandine Dozières-Puyravel, Frédéric Ebstein, Geoffroy Delplancq, Karun K. Singh, Elke Krüger, Yannis Duffourd, Laurence Faivre, Jean-Marc Costa, Barbara A. Zieba, Antonio Vitobello, Detlef Trost, Aïcha Boughalem, Stéphane Auvin, Sandro Klafack, Christel Thauvin-Robinet, Alain Verloes, and Laurence Duplomb

Subjects
Male, 0301 basic medicine, Heterozygote, Candidate gene, alpha7 Nicotinic Acetylcholine Receptor, Mutation, Missense, Chromosome Disorders, 030105 genetics & heredity, Mice, 03 medical and health sciences, Epilepsy, Seizures, Intellectual Disability, Exome Sequencing, Genetics, medicine, Animals, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Exome sequencing, Chromosomes, Human, Pair 15, Deubiquitinating Enzymes, business.industry, Homozygote, Proteasome complex, medicine.disease, Penetrance, Hypotonia, Phenotype, 030104 developmental biology, Female, Chromosome Deletion, medicine.symptom, business
Abstract

Heterozygous microdeletions of chromosome 15q13.3 (MIM: 612001) show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Rare patients carrying homozygous deletions show more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth. For years, CHRNA7 (MIM: 118511), was considered the candidate gene that could account for this syndrome. However, recent studies in mouse models have shown that OTUD7A/CEZANNE2 (MIM: 612024), which encodes for an ovarian tumor (OTU) deubiquitinase, should be considered the critical gene responsible for brain dysfunction. In this study, a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy was referred to our genetics center. Trio exome sequencing (tES) analysis identified a homozygous OTUD7A missense variant (NM_130901.2:c.697C>T), predicted to alter an ultraconserved amino acid, p.(Leu233Phe), lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient-derived fibroblasts and in OTUD7A knockout HAP1 cell line. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early-onset epileptic encephalopathy and proteasome dysfunction.

Published
2020

3. A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort

Author

Philippine Garret, Martin Chevarin, Antonio Vitobello, Simon Verdez, Cyril Fournier, Alain Verloes, Emilie Tisserant, Pierre Vabres, Orlane Prevel, Christophe Philippe, Anne-Sophie Denommé-Pichon, Ange-Line Bruel, Frédéric Tran Mau-Them, Hana Safraou, Aïcha Boughalem, Jean-Marc Costa, Detlef Trost, Christel Thauvin-Robinet, Laurence Faivre, and Yannis Duffourd

Subjects
Genetics, Genetics (clinical)
Abstract

About 0.3% of all variants are due to de novo mobile element insertions (MEIs). The massive development of next-generation sequencing has made it possible to identify MEIs on a large scale. We analyzed exome sequencing (ES) data from 3232 individuals (2410 probands) with developmental and/or neurological abnormalities, with MELT, a tool designed to identify MEIs. The results were filtered by frequency, impacted region and gene function. Following phenotype comparison, two candidates were identified in two unrelated probands. The first mobile element (ME) was found in a patient referred for poikilodermia. A homozygous insertion was identified in the FERMT1 gene involved in Kindler syndrome. RNA study confirmed its pathological impact on splicing. The second ME was a de novo Alu insertion in the GRIN2B gene involved in intellectual disability, and detected in a patient with a developmental disorder. The frequency of de novo exonic MEIs in our study is concordant with previous studies on ES data. This project, which aimed to identify pathological MEIs in the coding sequence of genes, confirms that including detection of MEs in the ES pipeline can increase the diagnostic rate. This work provides additional evidence that ES could be used alone as a diagnostic exam.

Published
2021

4. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

Author

Arthur Sorlin, Antonio Vitobello, Benoit Daubail, Christel Thauvin-Robinet, Marie Hervieu-Bègue, Laurence Faivre, Agnès Fromont, Ange-Line Bruel, Frédéric Tran Mau-Them, Thibault Moreau, Julian Delanne, Guy-Victor Osseby, Quentin Thomas, Patrick Callier, Christophe Philippe, Sébastien Moutton, Maurice Giroud, Anne-Sophie Denommé-Pichon, Agnès Jacquin-Piques, Sophie Nambot, Yannis Duffourd, Philippine Garret, Y Béjot, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Neurophysiologie Clinique (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Proband, Pediatrics, medicine.medical_specialty, Movement disorders, Neurology, Neurodegeneration with brain iron accumulation, [SDV]Life Sciences [q-bio], Encephalopathy, Neurogenetics, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, Humans, Medicine, Exome, Clinical significance, 030212 general & internal medicine, Genetic Testing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Nervous System Diseases, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

Published
2021

5. Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants

Author

Sebastien Moutton, Antonio Vitobello, Laurence Faivre, Christophe Philippe, Christel Thauvin-Robinet, Philippine Garret, Thibaud Jouan, Martin Chevarin, Benoit Urteaga, Yannis Duffourd, Sophie Nambot, Frédéric Tran-Mau-Them, Arthur Sorlin, François Lecoquierre, Ange-Line Bruel, and Christine Coubes

Subjects
Male, 0301 basic medicine, Candidate gene, Developmental Disabilities, Mutation, Missense, 030105 genetics & heredity, Biology, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Databases, Genetic, Intellectual disability, medicine, Humans, Missense mutation, Exome, Genetic Predisposition to Disease, Genetic Testing, Autistic Disorder, Gene, Genetics (clinical), Exome sequencing, Genetics, Computational Biology, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, medicine.disease, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Female, Transcription Factors
Abstract

Next-generation sequencing has revealed the major impact of de novo variants (DNVs) in developmental disorders (DD) such as intellectual disability, autism, and epilepsy. However, a substantial fraction of these predicted pathogenic DNVs remains challenging to distinguish from background DNVs, notably the missense variants acting via nonhaploinsufficient mechanisms on specific amino acid residues. We hypothesized that the detection of the same missense variation in at least two unrelated individuals presenting with a similar phenotype could be a powerful approach to reveal novel pathogenic variants. We looked for variations independently present in both our database of >1200 solo exomes and in denovo-db, a large, publicly available collection of de novo variants identified in patients with DD. This approach identified 30 variants with strong evidence of pathogenicity, including variants already classified as pathogenic or probably pathogenic by our team, and also several new variants of interest in known OMIM genes or in novel genes. We identified FEM1B and GNAI2 as good candidate genes for syndromic intellectual disability and confirmed the implication of ACTL6B in a neurodevelopmental disorder. Annotation of local variants with denovo-db can highlight missense variants with high potential for pathogenicity, both facilitating the time-consuming reanalysis process and allowing novel DD gene discoveries.

Published
2019

6. Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

Author

Jennifer E. Posey, Arthur Sorlin, Fatema Al Zahrani, Jérôme Govin, Nathalie Marle, Thomas Besnard, Anne-Sophie Denommé-Pichon, Sebastien Moutton, Jill A. Madden, Patrick Callier, Christophe Philippe, Eleina M. England, Julian Delanne, Benjamin Cogné, Ange-Line Bruel, Pankaj B. Agrawal, Maria Iascone, Tabib Dabir, Solène Conrad, Thierry Gautier, Quentin Thomas, Nebal Waill Saadi, Lydie Burglen, Laurence Duplomb, Fowzan S. Alkuraya, Yannis Duffourd, Sylvie Nguyen, Siddharth Banka, Dana Marafi, Marjolaine Willems, Christel Thauvin-Robinet, Philippine Garret, Laurence Faivre, Frédéric Tran Mau-Them, Antonio Vitobello, James R. Lupski, Adam Jackson, Diana Rodriguez, Alice Masurel, Romano Tenconi, Martin Chevarin, and Bertand Isidor

Subjects
0301 basic medicine, Genetics, Candidate gene, Heterozygote, Epilepsy, ADP ribosylation factor, In silico, Heterozygote advantage, Haploinsufficiency, 030105 genetics & heredity, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, Intellectual Disability, medicine, Guanine Nucleotide Exchange Factors, Humans, Guanine nucleotide exchange factor, Genetics (clinical), Minigene
Abstract

PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.RESULTS: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.CONCLUSION: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.

Published
2021
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7. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome

Author

V. Carmignac, Yannis Duffourd, Geneviève Bernard, Bénédicte Demeer, Didier Bessis, Christel Thauvin, Bernard Devauchelle, Odile Boute, Philippine Garret, Arthur Sorlin, Esther Carmi, Julien Thevenon, Veronica A. Kinsler, Arnaud Lafon, Alain Bron, S.S. Kholmanskikh, Catherine Gondry-Jouet, William B. Dobyns, Guillaume Captier, Paul Kuentz, Pierre Vabres, Jean Benoît Courcet, Laurent Guibaud, David Geneviève, Jean Baptiste Rivière, Satyamaanasa Polubothu, Francesca Faravelli, Judith St-Onge, Laurence Faivre, M. Elizabeth Ross, Michèle Mathieu-Dramard, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Weill Cornell Medicine, CHU Amiens-Picardie, MCGill University Health Centre, Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Dermatology Office, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), McGill University = Université McGill [Montréal, Canada], UMR 1231, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), MCGill University, ProdInra, Archive Ouverte, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Genetics, 0303 health sciences, RHOA, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Mosaic (geodemography), 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract

Published Erratum: Correction to: Nature Genetics 51: 1438–1441 https://doi.org/10.1038/s41588-019-0498-4, published online 30 September 2019.In the version of this article initially published, authors Bénédicte Demeer and Bernard Devauchelle were missing the affiliation EA CHIMERE–7516, Université Picardie Jules Verne, Amiens, France. The error has been corrected in the HTML and PDF versions of the article.; An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

8. Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome

Author

M. Elizabeth Ross, Philippine Garret, Jean Benoît Courcet, Guillaume Captier, Francesca Faravelli, Michèle Mathieu-Dramard, Veronica A. Kinsler, Bernard Devauchelle, Bénédicte Demeer, David Geneviève, S.S. Kholmanskikh, Odile Boute, Christel Thauvin, Satyamaanasa Polubothu, Paul Kuentz, Julien Thevenon, Esther Carmi, Arnaud Lafon, William B. Dobyns, Yannis Duffourd, Geneviève Bernard, Judith St-Onge, Laurence Faivre, Jean Baptiste Rivière, Arthur Sorlin, Pierre Vabres, Catherine Gondry-Jouet, Alain Bron, Didier Bessis, V. Carmignac, Laurent Guibaud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Cornell Medicine, CHU Amiens-Picardie, McGill University = Université McGill [Montréal, Canada], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Dermatology Office, Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), This work was funded by the Agence Nationale de la Recherche (grant no. ANR-13-PDOC-0029 to J.-B.R.), the Programme Hospitalier de Recherche Clinique National 2010 (grant no. NCT01950975 to P.V.), the NIH (grant no. HD067244 to M.E.R.) and the Societe Francaise de Dermatologie. G.B. has received a Research Scholar Junior 1 (2012-2016) salary award from the Fonds de Recherche du Quebec en Sante and the New Investigator salary award (2017-2022) from the Canadian Institute for Health Research (no. MOP-G-287547, file no. 24805)., ProdInra, Migration, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
RHOA, Zygote, Skin Pigmentation, Disease, Article, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, Hypopigmentation, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Extramural, Mosaicism, Neurocutaneous Syndromes, medicine.disease, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Mutation, Etiology, Cancer research, biology.protein, medicine.symptom, rhoA GTP-Binding Protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Hypopigmentation along Blaschko’s lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental, and acral anomalies. Our findings pave the way towards elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease., Editorial summary Postzygotic inactivating mutations in RHOA cause a mosaic neuroectodermal syndrome characterized by linear hypopigmentation, leukoencephalopathy, and craniofacial anomalies, highlighting the role of RHOA in human development and disease.

Published
2016

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