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1. P428: De novo truncating variants in ZNF865: A putative cause of a neurodevelopmental disorder

Author

Sam Bradbrook, Gail Graham, Melissa Carter, Maria Kibaek, Martin Larsen, Christina Fagerberg, Katherine Dawson, Cheryl Meuter, Alexander Pepler, Thomas Besnard, Bertrand Isidor, Stéphane Bezieau, Benjamin Cogné, Marie Vincent, Katherine Bjorgo, Thomas Courtin, Lisa Emrick, Jill Rosenfeld, Undiagnosed Diseases Network, Julian Martinez-Agosto, Mathilde Heulin, Gilles Morin, Pauline Monin, Louis Januel, Marie-Noëlle Bonnet-Dupeyron, Mathilde Pujalte, Kim Worley, Monika Weisz-Hubshman, Patricia Dickson, Michelle Thompson, and Julien Marcadier

Subjects
Genetics, QH426-470, Medicine
Published
2024
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2. Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients

Author

Véronique Picard, Corinne Guitton, Isabelle Thuret, Christian Rose, Laurence Bendelac, Kaldoun Ghazal, Patricia Aguilar-Martinez, Catherine Badens, Claire Barro, Claire Bénéteau, Claire Berger, Pascal Cathébras, Eric Deconinck, Jacques Delaunay, Jean-Marc Durand, Nadia Firah, Frédéric Galactéros, Bertrand Godeau, Xavier Jaïs, Jean-Pierre de Jaureguiberry, Camille Le Stradic, François Lifermann, Robert Maffre, Gilles Morin, Julien Perrin, Valérie Proulle, Marc Ruivard, Fabienne Toutain, Agnès Lahary, and Loïc Garçon

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a ‘Gardos channelopathy’. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Published
2019
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3. Severe Psychomotor Delay in a Severe Presentation of Cat-Eye Syndrome

Author

Guillaume Jedraszak, Aline Receveur, Joris Andrieux, Michèle Mathieu-Dramard, Henri Copin, and Gilles Morin

Subjects
Genetics, QH426-470
Abstract

Cat-eye syndrome is a rare genetic syndrome of chromosomal origin. Individuals with cat-eye syndrome are characterized by the presence of preauricular pits and/or tags, anal atresia, and iris coloboma. Many reported cases also presented with variable congenital anomalies and intellectual disability. Most patients diagnosed with CES carry a small supernumerary bisatellited marker chromosome, resulting in partial tetrasomy of 22p-22q11.21. There are two types of small supernumerary marker chromosome, depending on the breakpoint site. In a very small proportion of cases, other cytogenetic anomalies are reportedly associated with the cat-eye syndrome phenotype. Here, we report a patient with cat-eye syndrome caused by a type 1 small supernumerary marker chromosome. The phenotype was atypical and included a severe developmental delay. The use of array comparative genomic hybridization ruled out the involvement of another chromosomal imbalance in the neurological phenotype. In the literature, only a few patients with cat-eye syndrome present with a severe developmental delay, and all of the latter carried an atypical partial trisomy 22 or an uncharacterized small supernumerary marker chromosome. Hence, this is the first report of a severe neurological phenotype in cat-eye syndrome with a typical type 1 small supernumerary marker chromosome. Our observation clearly complicates prognostic assessment, particularly when cat-eye syndrome is diagnosed prenatally.

Published
2015
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6. Kleefstra syndrome: Recurrence in siblings due to a paternal mosaic mutation

Author

Sara Costantini, Gilles Morin, Guillaume Jedraszak, Emilie Lacot-Leriche, Amélie Piton, Florence Jobic, Anne-Gaëlle Le Moing, and Michèle Mathieu-Dramard

Subjects
Genetics, business.industry, Genetic counseling, Macrocephaly, Genetic disorder, medicine.disease, Hypotonia, EHMT1, Autism spectrum disorder, Mutation (genetic algorithm), medicine, medicine.symptom, business, Genetics (clinical), Kleefstra Syndrome
Abstract

Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.

Published
2021
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8. Clinical and neuroimaging findings in 33 patients with <scp>MCAP</scp> syndrome: A survey to evaluate relevant endpoints for future clinical trials

Author

Florence Petit, Fabienne Giuliano, Juliette Mazereeuw-Hautier, Marjolaine Willems, Christel Thauvin-Robinet, Patricia Blanchet, Laurence Faivre, Elodie Gautier, Anne-Claire Bursztejn, Renaud Touraine, Annick Toutain, Frederico Di Rocco, Maxime Luu, Patrick Edery, Arthur Sorlin, Jean-Luc Alessandri, Nicolas Chassaing, Alice Goldenberg, Christine Chiaverini, Fanny Morice-Picard, Aurore Garde, Stéphanie Arpin, Massimiliano Rossi, Marc Bardou, Claire Nicolas, Gilles Morin, Jenny Cornaton, Cyril Mignot, Christophe Philippe, V. Carmignac, Rodolphe Dard, Joelle Roume, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Pierre Vabres, Didier Lacombe, Diane Doummar, Lucile Pinson, Christine Coubes, Laurent Guibaud, Olivia Boccara, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cutis marmorata, Adolescent, Class I Phosphatidylinositol 3-Kinases, Neuroimaging, Context (language use), Skin Diseases, Vascular, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Genetics, Polymicrogyria, medicine, Humans, PROS, Abnormalities, Multiple, Telangiectasis, Megalencephaly, Child, MCAP syndrome, Genetics (clinical), Chiari malformation, Clinical Trials as Topic, business.industry, Macrocephaly, PIK3CA, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Clinical trial, 030104 developmental biology, Child, Preschool, Postnatal macrocephaly, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Forecasting, Ventriculomegaly
Abstract

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Published
2021
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9. Persistent Müllerian duct syndrome associated with genetic defects in the regulatory subunit of myosin phosphatase

Author

Jean-Yves Picard, Gilles Morin, Mojgan Devouassoux-Shisheboran, Jasper Van der Smagt, Serge Klosowski, Catherine Pienkowski, Peggy Pierre-Renoult, Cécile Masson, Christine Bole, and Nathalie Josso

Subjects
Male, Anti-Mullerian Hormone, Myosin-Light-Chain Phosphatase, Disorder of Sex Development, 46,XY, Reproductive Medicine, Rehabilitation, Obstetrics and Gynecology, Humans, DNA
Abstract

STUDY QUESTION Can mutations of genes other than AMH or AMHR2, namely PPP1R12A coding myosin phosphatase, lead to persistent Müllerian duct syndrome (PMDS)? SUMMARY ANSWER The detection of PPP1R12A truncation mutations in five cases of PMDS suggests that myosin phosphatase is involved in Müllerian regression, independently of the anti-Müllerian hormone (AMH) signaling cascade. WHAT IS KNOWN ALREADY Mutations of AMH and AMHR2 are detectable in an overwhelming majority of PMDS patients but in 10% of cases, both genes are apparently normal, suggesting that other genes may be involved. STUDY DESIGN, SIZE, DURATION DNA samples from 39 PMDS patients collected from 1990 to present, in which Sanger sequencing had failed to detect biallelic AMH or AMHR2 mutations, were screened by massive parallel sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS To rule out the possibility that AMH or AMHR2 mutations could have been missed, all DNA samples of good quality were analyzed by targeted next-generation sequencing. Twenty-four samples in which the absence of AMH or AMHR2 biallelic mutations was confirmed were subjected to whole-exome sequencing with the aim of detecting variants of other genes potentially involved in PMDS. MAIN RESULTS AND THE ROLE OF CHANCE Five patients out of 24 (21%) harbored deleterious truncation mutations of PP1R12A, the gene coding for the regulatory subunit of myosin phosphatase, were detected. In addition to PMDS, three of these patients presented with ileal and one with esophageal atresia. The congenital abnormalities associated with PMDS in our patients are consistent with those described in the literature for PPP1R12A variants and have never been described in cases of AMH or AMHR2 mutations. The role of chance is therefore extremely unlikely. LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is the lack of experimental validation of the role of PPP1R12A in Müllerian regression. Only circumstantial evidence is available, myosin phosphatase is required for cell mobility, which plays a major role in Müllerian regression. Alternatively, PPP1R12A mutations could affect the AMH transduction pathway. WIDER IMPLICATIONS OF THE FINDINGS The study supports the conclusion that failure of Müllerian regression in males is not necessarily associated with a defect in AMH signaling. Extending the scope of molecular analysis should shed light upon the mechanism of the initial steps of male sex differentiation. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by la Fondation Maladies Rares, GenOmics 2021_0404 and la Fondation pour la Recherche Médicale, grant EQU201903007868. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Published
2022

10. Overlapping phenotypes between <scp>SHORT</scp> and Noonan syndromes in patients with <scp> PTPN11 </scp> pathogenic variants

Author

Charles Marques, Yline Capri, Anne Guimier, A. Micheil Innes, Jeanne Amiel, Martine Auclair, Julien Thevenon, David A. Dyment, Gilles Morin, Christel Thauvin-Robinet, Corinne Vigouroux, Emmanuelle Ranza, Michèle Mathieu-Dramard, Alain Verloes, and Laurence Faivre

Subjects
Male, musculoskeletal diseases, 0301 basic medicine, MAPK/ERK pathway, congenital, hereditary, and neonatal diseases and abnormalities, MAP Kinase Signaling System, Protein Tyrosine Phosphatase, Non-Receptor Type 11, 030105 genetics & heredity, Biology, Gene product, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Metabolic Diseases, Genetics, medicine, Humans, Missense mutation, skin and connective tissue diseases, Protein kinase B, Growth Disorders, Genetics (clinical), Genetic heterogeneity, Noonan Syndrome, Genetic Variation, medicine.disease, PTPN11, Nephrocalcinosis, Phenotype, 030104 developmental biology, SHORT syndrome, Hypercalcemia, Noonan syndrome, Female, Mitogen-Activated Protein Kinases, Signal Transduction
Abstract

Overlapping syndromes such as Noonan, Cardio-Facio-Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease-causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease-causing gene being PIK3R1. Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling.

Published
2020
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13. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author

Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California

Subjects
0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Published
2019
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14. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, SHARP, Male, obesity, genotype-phenotype correlations, Autism Spectrum Disorder, PROTEIN, Chromosome Disorders, Haploinsufficiency, RNA-Binding Protein, PHENOTYPE CORRELATIONS, 1p36, distal 1p36 deletion syndrome, DNA methylome analysis, episignature, neurodevelopmental disorder, proximal 1p36 deletion syndrome, SPEN, X chromosome, Adolescent, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult, 0302 clinical medicine, Neurodevelopmental disorder, Neurodevelopmental Disorder, Intellectual disability, MOLECULAR CHARACTERIZATION, Genetics (clinical), Genetics, DNA methylome analysi, SPLIT-ENDS, Hypotonia, Autism spectrum disorder, MONOSOMY 1P36, Pair 1, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, DNA-Binding Protein, Biology, genotype-phenotype correlation, Chromosomes, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Report, REVEALS, medicine, Epigenetics, Preschool, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 1p36 deletion syndrome, IDENTIFICATION, MUTATIONS, medicine.disease, GENE, 030104 developmental biology, Chromosome Disorder, 030217 neurology & neurosurgery, Epigenesis
Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

16. Author response for 'Clinical and neuroimaging findings in 33 patients with MCAP syndrome: a survey to evaluate relevant endpoints for future clinical trials'

Author

Florence Petit, Juliette Mazereeuw-Hautier, Christine Coubes, Patricia Blanchet, Jenny Cornaton, Frederico Di Rocco, Fabienne Giuliano, Arthur Sorlin, Elodie Gautier, Laurent Guibaud, Renaud Touraine, Massimiliano Rossi, Christophe Philippe, Jean-Luc Alessandri, Joelle Roume, Patrick Edery, Gilles Morin, Christine Chiaverini, Diane Doummar, Michèle Mathieu-Dramard, Olivia Boccara, Philippe Khau Van Kien, Aurore Garde, Claire Nicolas, Maxime Luu, Lucile Pinson, Nicolas Chassaing, Fanny Morice-Picard, Christel Thauvin-Robinet, Rodolphe Dard, Cyril Mignot, Marc Bardou, V. Carmignac, Pierre Vabres, Alice Goldenberg, Laurence Faivre, Didier Lacombe, Annick Toutain, Stéphanie Arpin, Marjolaine Willems, and Anne-Claire Bursztejn

Subjects
Clinical trial, medicine.medical_specialty, Neuroimaging, business.industry, medicine, Intensive care medicine, business
Published
2020
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17. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Author

Florence Petit, Clémence Vanlerberghe, Thomas Smol, Fabienne Giuliano, M.F. Odou, Sylvie Manouvrier-Hanu, Perrine Brunelle, William Dufour, Malika Balduyck, Fabienne Escande, Jamal Ghoumid, Marion Gérard, Philippe Khau Van Kien, Gilles Morin, Cindy Colson, Alice Goldenberg, Elise Brischoux-Boucher, Anne Dieux, Daphné Lehalle, Anne-Sophie Jourdain, Sébastien Moutton, Simon Boussion, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Laboratoire Pierre Süe (LPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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, Inserm, Université de Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Maladies RAres du DÉveloppement embryonnaire et du Métabolisme : du phénotype au génotype et à la Fonction (RADEME) - ULR 7364, CIC CHU ( Lille)/inserm, Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Service de Génétique Clinique [CHU Caen], Université de Lausanne = University of Lausanne [UNIL], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME], and Richard, Nicolas

Subjects
Male, Candidate gene, limb malformation, molecular diagnosis, targeted high-throughput sequencing, genetics, DNA Copy Number Variations, DNA Mutational Analysis, Limb Deformities, Congenital, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, DNA sequencing, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Multiplex, Genetic Testing, Uncertain significance, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Likely pathogenic, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Phenotype, 3. Good health, Radiography, Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female
Abstract

International audience; Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.

Published
2020
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19. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Author

Dominique Martin-Coignard, Olivier Pincemaille, Claire de Barace, Nathalie Boddaert, Michel Polak, Tiffany Pascreau, Nathalie Seta, Christine Francannet, Gilles Morin, Valérie Cormier-Daire, François Labarthe, Manuel Schiff, Alexis Brice, Anaïs Brassier, Arnaud Bruneel, Patrick Edery, Alina Arion, Isabelle Fontan, Brigitte Chabrol, Cyril Gitiaux, Emmanuel de Maistre, Anne de Saint-Martin, Valérie Drouin-Garraud, Maud Bidet, Magali Barth, Catherine Bloch, Thierry Dupré, Céline Roda, Nathalie Bednarek, Sandrine Vuillaumier-Barrot, Marie-Chantal Chevalier, Géraldine Viot, François Feillet, Annick Toutain, Sylvie Lamoureux, Christel Thauvin-Robinet, Marie Hully, Delphine Borgel, Cyril Mignot, Nathalie Dorison, Bernard Echenne, Agathe Roubertie, Delphine Héron, Roger Buissonnière, Marie-Lorraine Monin, and Pascale de Lonlay

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Pericarditis, Congenital Disorders of Glycosylation, 0302 clinical medicine, Tubulopathy, Hydrops fetalis, Genetics, Humans, Medicine, Hypoalbuminemia, Child, Alleles, Genetic Association Studies, Genetics (clinical), business.industry, Infant, medicine.disease, Hypotonia, Phenotype, 030104 developmental biology, Amino Acid Substitution, Phosphotransferases (Phosphomutases), Inborn error of metabolism, Child, Preschool, Mutation, Female, medicine.symptom, business, Nephrotic syndrome, Congenital disorder of glycosylation, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Published
2017
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20. Prenatal diagnosis of femoral facial syndrome: Three case reports and literature review

Author

Céline Klein, Catherine Gondry-Jouet, J. Gondry, Gilles Morin, Philippe Naepels, Bénédicte Demeer, Guillaume Jedraszak, Marion Luisin, J. Chevreau, Anne Dieux-Coeslier, and Michèle Mathieu-Dramard

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cleft Lip, Prenatal diagnosis, 030105 genetics & heredity, Ultrasonography, Prenatal, 03 medical and health sciences, Fetus, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, Retrognathia, Genetics, medicine, Humans, Abnormalities, Multiple, Femur, Exome, Genetics (clinical), Comparative Genomic Hybridization, 030219 obstetrics & reproductive medicine, Pierre Robin Syndrome, business.industry, Infant, Newborn, Karyotype, Anatomy, Middle Aged, medicine.disease, Hypoplasia, Diabetes, Gestational, Agenesis, Female, Abnormality, business, Comparative genomic hybridization
Abstract

Facial femoral syndrome (FFS) is a rare congenital abnormality, also known as femoral hypoplasia-unusual facies syndrome, characterized by variable degrees of femoral hypoplasia, associated with specific facial features. Other organ malformations are sometimes present. Most cases are sporadic, but rare family observations suggest genetic origin. However, no chromosomal or genetic abnormalities have ever been incriminated. We conducted a comprehensive literature review and added three new unreported observations. Through these 92 cases, authors aimed to determine sonographic signs that should direct towards diagnosis, and discuss potential genetic etiology. Diagnosis was suspected prenatally in 27.2% of cases, and maternal diabetes was found in 42.4% of patients. When fetal karyotype was available, it was normal in 97.1% of cases, but genomic variations of unknown significance were discovered in all three cases in which array comparative genomic hybridization (CGH) techniques were applied. Femoral affection defining FFS was hypoplasia in 78.3% of cases, agenesis in 12%, and both in 9.8%. Affection was bilateral in 84.8% of cases. Retrognathia was present in 65.2% of cases, cleft lip and/or palate in 63%, and other organ malformations in 53.3%. Intellectual development was normal in 79.2% of cases. Better prenatal recognition of this pathology, notably frequently associated malformations, should lead to a more precise estimation of functional prognosis. It seems likely that today's tendency to systematically employ array-CGH and exome/genome sequencing methods to investigate malformative sequences will allow the identification of a causal genetic abnormality in the near future.

Published
2017
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21. New intragenic rearrangements in non‐Finnish mulibrey nanism

Author

Guillaume Jedraszak, Jacques Rochette, Estelle Cadet, Rosalie Cabry, Catherine Vincent-Delorme, Michèle Mathieu-Dramard, Gilles Morin, Henri Copin, and Florence Jobic

Subjects
Male, 0301 basic medicine, Mulibrey nanism, Adolescent, Ubiquitin-Protein Ligases, Nonsense mutation, Alu element, Biology, Bioinformatics, medicine.disease_cause, Tripartite Motif Proteins, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, medicine, Humans, Child, Gene, Genetics (clinical), Gene Rearrangement, Mutation, Breakpoint, Infant, Nuclear Proteins, Prognosis, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, 030220 oncology & carcinogenesis, Female, France, Mulibrey Nanism
Abstract

Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.

Published
2017
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22. Value of molecular typing in the assessment of bacterial translocation during coagulase-negative staphylococcal bacteremia in preterm infants

Author

Maurice Biendo, André Léké, Gilles Morin, Geraldine Amar, Guy Kongolo, Sabrina Goudjil, and Bertin Elion Dzon

Subjects
Molecular typing, business.industry, Staphylococcal bacteremia, Medicine, Coagulase, Bacterial translocation, business, Value (mathematics), Microbiology
Abstract

Background One hundred fifty-seven preterm infants enrolled in the study were hospitalized between 2012-2014 at Amiens-Picardie University Hospital.Only 28 (17.8%) of these children who had experienced at least one episode of secondary Coagulase-negative Staphylococcal bacteremia with concomitant positive stool cultures were included in this study.The purpose of this study was to assess the rate of intestinal bacterial translocation associated with these infections. Methods Blood cultures and stool cultures were performed in the context of this study. All isolates of Staphylococcus spp were examined by MALDI-TOF MS. Antibiotic susceptibility and genotyping were also performed. Results Sixteen resistance patterns were identified from blood and stool based on antibiotic susceptibility testing. Ten of the Coagulase-negative Staphylococcus strains isolated from blood samples exhibited R pattern e (35.7%) and eleven of the Coagulase-negative Staphylococcus strains isolated from stool samples exhibited R pattern e (39.2%). Blood culture results were concordant with stool culture results in 53.5% of cases and discordant in 46.5% of cases.Fifteen isolates exhibited three ERIC-2 (A, B, C) and three RAPD-PCR (D, E, F) patterns. ERIC-2 patterns comprised A ( S. epidermidis isolates); B ( S. haemolyticus isolates) and C ( unidentified Coagulase-negative Staphylococcus isolates). RAPD patterns consisted of D ( unidentified Coagulase-negative Staphylococcus isolates), E ( S. haemolyticus isolates), and F ( S. epidermidis isolates). Conclusion Bacterial translocation from the intestinal tract was likely source of Coagulase-negative Staphylococcal bacteremia in hospitalized preterm infants.

Published
2019
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23. Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients

Author

Agnès Lahary, Jean-Pierre de Jaureguiberry, Fabienne Toutain, Véronique Picard, Patricia Aguilar-Martinez, Bertrand Godeau, Xavier Jaïs, Catherine Badens, Robert Maffre, Christian Rose, Isabelle Thuret, François Lifermann, Corinne Guitton, Frédéric Galactéros, Gilles Morin, Nadia Firah, Marc Ruivard, Claire Berger, Valérie Proulle, Camille Le Stradic, Pascal Cathébras, Laurence Bendelac, Jacques Delaunay, Julien Perrin, Claire Barro, Claire Bénéteau, Eric Deconinck, Khaldoun Ghazal, Loïc Garçon, Jean-Marc Durand, roussel, pascale, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Saclay, Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Saint Vincent de Paul de Lille, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Grenoble, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Etienne, Centre Catherine-de-Sienne [Nantes] (CCS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier de Pau, Hôpital Henri Mondor, Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), Université de Bretagne Sud (UBS), Centre Hospitalier de Dax, CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, CHU Pontchaillou [Rennes], CHU Rouen, Normandie Université (NU), Université de Picardie Jules Verne (UPJV), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Pediatrics, medicine.medical_specialty, Iron Overload, Anemia, Hydrops Fetalis, medicine.medical_treatment, Splenectomy, Mutation, Missense, Disease, Anemia, Hemolytic, Congenital, Hemolysis, Article, Ion Channels, 03 medical and health sciences, 0302 clinical medicine, Channelopathy, Pregnancy, Edema, Humans, Medicine, Missense mutation, Family, Retrospective Studies, 030304 developmental biology, 0303 health sciences, business.industry, Red Cell & its Disorders, Thrombosis, Retrospective cohort study, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Intermediate-Conductance Calcium-Activated Potassium Channels, medicine.disease, 3. Good health, Mutation, Mutation (genetic algorithm), Channelopathies, Female, business, 030215 immunology
Abstract

International audience; We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a ‘Gardos channelopathy’. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Published
2019
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24. HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients

Author

Mohammed Adel Nouri, Johannes A. Mayr, Oliver Brandau, Holger Prokisch, Saskia B. Wortmann, Gilles Morin, Reka Kovacs-Nagy, Florence van den Broek, Nebal Waill Saadi, and Maria Al Nouri

Subjects
0301 basic medicine, Male, Movement disorders, Mitochondrial Diseases, Mitochondrial disease, Developmental Disabilities, Bioinformatics, Infant, Newborn, Diseases, 03 medical and health sciences, Epilepsy, Fatal Outcome, Tremor, medicine, Humans, Exome, Movement Disorders, business.industry, Genetic heterogeneity, DNAJC19, Infant, Newborn, Infant, General Medicine, 3-Methylglutaconic Aciduria, High-Temperature Requirement A Serine Peptidase 2, medicine.disease, Dystonia, 030104 developmental biology, Inborn error of metabolism, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), medicine.symptom, business, Respiratory Insufficiency, Metabolism, Inborn Errors
Abstract

Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.

Published
2018

25. Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts

Author

Jean-Marie Cuisset, Isabelle Kim, Marie-Adélaïde Bout, Stéphanie Moortgat, David Cheillan, Marie Joncquel-Chevalier Curt, Monique Fontaine, Soumeya Bekri, Alexandre Moerman, Guillemette Huet, Joseph Vamecq, Gilles Morin, Centre de Génétique Humaine (Institut de Pathologie et de Génétique, Charleroi), Institut de Pathologie et de Génétique, Charleroi, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service Maladies Héréditaires du Métabolisme, Centre de Biologie Est, Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, Male, Bioenergetics, diagnosis, guanidinoacetate, UPLC/tandem MS, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Biochemistry, Plasma Membrane Neurotransmitter Transport Proteins, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, tandem mass-spectrometry, Female carriers, Child, Incubation, metabolites, chemistry.chemical_classification, Genetics & Heredity, slc6a8 deficiency, D-3-creatine, SLC6A8 gene, Research & Experimental, Prognosis, urine, 3. Good health, Child, Preschool, RNA splicing, Medicine, Female, inborn-errors, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Creatine, 03 medical and health sciences, Endocrinology & Metabolism, Guanidino, Internal medicine, Genetics, medicine, Humans, Molecular Biology, Gene, plasma, Brain Diseases, Metabolic, Inborn, Infant, Transporter, Fibroblasts, X-linked disorder, 030104 developmental biology, Enzyme, chemistry, Case-Control Studies, methyltransferase gamt deficiency, Mutation, mental-retardation, Mental Retardation, X-Linked, body-fluids, Creatine transporter, Male hemizygotes, 030217 neurology & neurosurgery, Fetal bovine serum, Follow-Up Studies
Abstract

International audience; Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D-3-creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended. Together, these measures decreased, by a first order of magnitude, creatine concentrations in the incubation medium at the start of creatine-uptake studies and allowed to functionally discriminate between 4 hemizygous male and 4 heterozygous female patients with X-linked SLC6A8 deficiency, and between this cohort of eight patients and controls. The functional assay corroborated genetic diagnosis of SLC6A8 deficiency. Gene anomalies in our small cohort included splicing site (c.912G \textgreater A [p.Ile260_Gln304del], c.778-2A \textgreater G and c.1495 + 2 T \textgreater G), substitution (c.407C \textgreater T) [p.Ala136Val] and deletion (c.635\₆36delAG [p.Glu212Valfs*84] and c.1324delC [p.Gln442Lysfs*21]) variants with reduced creatine transporter function validating their pathogenicity, including that of a previously unreported c.1324delC variant. The present assay adaptations provide an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations. It might apply to drug testing or other evaluations in the genetic and metabolic horizons covered by the emerging functions of creatine and its transporter, in a way, however, requiring and completed by additional studies on female patients and blood-brain barrier permeability properties of selected compounds. As a whole, the proposed assay of creatine transporter positively adds to currently existing measurements of this transporter activity, and determining on a large scale the extent of its exact suitability to detect female patients should condition in the future its transfer in clinical practice.

Published
2018
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26. FOXE3 mutations: Genotype-phenotype correlations

Author

H. Dollfus, Gilles Morin, J. C. Kaplan, Christine Francannet, Hélène Colineaux, Nicola K. Ragge, Daphné Lehalle, Nicolas Chassaing, Julie Plaisancié, Patrick Calvas, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Oxford Brookes University, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Genetics in Ophthalmology (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Génétique Clinique et Oncogénétique, Centre Hospitalier Universitaire d'Amiens Picardie, Amiens, France, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, Male, MESH: Developmental Disabilities / physiopathology, genetic structures, genotype-phenotype correlations, Developmental Disabilities, anophthalmia, Microphthalmia, MESH: Forkhead Transcription Factors / genetics, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Microphthalmos, Eye Abnormalities, MESH: Developmental Disabilities / genetics, Genetics (clinical), Genetics, Forkhead Transcription Factors, MESH: Aphakia / physiopathology, Phenotype, 3. Good health, cataract, Mutation (genetic algorithm), Female, MESH: Mutation, Genetic counseling, MESH: Eye Abnormalities / physiopathology, Biology, MESH: Aphakia / genetics, 03 medical and health sciences, Dysgenesis, MESH: Genetic Predisposition to Disease, medicine, Humans, Genetic Predisposition to Disease, Sclerocornea, Gene, MESH: Microphthalmos / physiopathology, Alleles, Anophthalmia, MESH: Humans, MESH: Alleles, aphakia, MESH: Microphthalmos / genetics, medicine.disease, eye diseases, MESH: Male, 030104 developmental biology, microphthalmia, MESH: Eye Abnormalities / genetics, Mutation, eye development, 030221 ophthalmology & optometry, anterior segment dysgenesis, FOXE3, sense organs, MESH: Female
Abstract

International audience; Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene-based therapies.

Published
2018
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27. Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome

Author

Amélie Ryckewaert, Nadine Jay, Aurélia Bertholet-Thomas, Gilles Morin, Georges Deschênes, Cyrielle Treard, Vincent Guigonis, Rémi Salomon, Denis Morin, Brigitte Llanas, Rosa Vargas-Poussou, Daniele Bruno, Stéphane Decramer, Djamal Djeddi, François Nobili, Anne Blanchard, Isabelle Vrillon, Tackwa Khalifeh, Christine Pietrement, Françoise Broux, Sophie Dreux, Isabelle Roncelin, Anne Legrand, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Toulouse [Toulouse], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Proband, Male, Pediatrics, Epidemiology, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, 030232 urology & nephrology, Critical Care and Intensive Care Medicine, 0302 clinical medicine, Mutation Rate, Pregnancy, Prenatal Diagnosis, Prevalence, Missense mutation, Frameshift Mutation, X chromosome, Sequence Deletion, Sanger sequencing, education.field_of_study, Pregnancy Outcome, genetic renal disease, Adaptor Proteins, 3. Good health, Phenotype, Nephrology, Cohort, symbols, Female, France, Polyhydramnios, medicine.medical_specialty, X Chromosome, RNA Splicing, Population, Bartter syndrome, Frameshift mutation, 03 medical and health sciences, symbols.namesake, pediatric nephrology, Antigens, Neoplasm, medicine, Humans, Genetic Predisposition to Disease, Antigens, education, Adaptor Proteins, Signal Transducing, Retrospective Studies, Transplantation, business.industry, Signal Transducing, Bartter Syndrome, Original Articles, medicine.disease, 030104 developmental biology, Mutation, molecular genetics, Neoplasm, business
Abstract

International audience; BACKGROUND AND OBJECTIVES: Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (n=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. RESULTS: We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. CONCLUSIONS: MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome.

Published
2018
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28. Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: A family report

Author

Gilles Morin, Karine Braun, Dominique Bremond-Gignac, Joris Andrieux, Amrathlal Rabbind Singh, Henri Copin, Matthieu Decamp, Jacques Rochette, Aline Receveur, Guillaume Jedraszak, and Michèle Mathieu

Subjects
Male, medicine.medical_specialty, Hormone Replacement Therapy, Chromosomes, Human, Pair 22, Endocrinology, Diabetes and Metabolism, Hypothalamus, Chromosome Disorders, Biology, Short stature, Growth hormone deficiency, Endocrinology, Internal medicine, medicine, Humans, Abnormalities, Multiple, Eye Abnormalities, Small supernumerary marker chromosome, In Situ Hybridization, Fluorescence, Chromosome Aberrations, Human Growth Hormone, Infant, Newborn, General Medicine, Aneuploidy, medicine.disease, Cat eye syndrome, Karyotyping, Pituitary Gland, Tetrasomy, Growth delay, medicine.symptom, Imperforate anus, Chromosome 22
Abstract

Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.

Published
2015
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29. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Author

C. Thauvin-Robinet, S. El Chehadeh, Irina Giurgea, Aurélie Bourchany, Frédéric Huet, Stanislas Lyonnet, P.O. Lafontaine, Alice Masurel-Paulet, Dominique Bremond-Gignac, Alice Goldenberg, J. Massy, Laurence Faivre, C. Paillot, Julien Thevenon, D. Thouvenin, Gilles Morin, Alain Bron, Catherine Creuzot-Garcher, Alice Duncombe, and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)

Subjects
Male, medicine.medical_specialty, Adolescent, genetic structures, Mowat–Wilson syndrome, Retinal Pigment Epithelium, Biology, Eye, Cataract, chemistry.chemical_compound, Atrophy, Intellectual Disability, Ophthalmology, Genetics, medicine, Humans, Hirschsprung Disease, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Iris (anatomy), Hyphema, Genetics (clinical), Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Retina, Facies, Optic Nerve, Retinal, Anatomy, medicine.disease, eye diseases, Coloboma, Repressor Proteins, medicine.anatomical_structure, chemistry, Child, Preschool, Lens (anatomy), Mutation, Microcephaly, Optic nerve, Female, sense organs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.

Published
2015
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30. Le Parti socialiste et les femmes à la Libération: un rendez-vous manqué ?

Author

Zancarini-Fournel, Michelle, Gilles, Morin, GENRE (LARHRA GENRE ), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Anne-Laure Ollivier, Noëlline Castagnez, Gilles Morin, Frédéric Cépède, École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), and Collet, Jean-Paul

Subjects
Parti socialiste, [SHS.HIST] Humanities and Social Sciences/History, France, [SHS.HIST]Humanities and Social Sciences/History, femmes, Libération
Abstract

Textes issus du colloque "De la Résistance à la restauration de la légalité républicaine : le rôle des socialistes français au regard de l'Europe", Paris, Sénat et Mairie de Paris, 20 et 21 novembre 2014, organisé par l'Office universitaire de recherche socialiste, la Fondation Jean Jaurès et le Centre d'histoire sociale du XXe siècle; International audience

Published
2016

31. Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Author

Thierry Bienvenu, Sarah Baer, Yves Alembik, Laurent Pasquier, A.S. Lebre, Elise Schaefer, Sylvie Sukno, Caroline Nava, Cindy Colson, Didier Lacombe, Michèle Mathieu-Dramard, Valérie Cormier-Daire, Thomas Smol, Delphine Héron, Alice Goldenberg, Odile Boute, Martine Doco-Fenzy, Julien Thevenon, David Geneviève, Boris Keren, Nicole Philip, Catherine Vincent-Delorme, Sophie Rondeau, Alexandra Afenjar, Bruno Delobel, Damien Haye, G. Boursier, Marjolaine Willems, Amélie Piton, Mélanie Fradin, Alice Masurel, A. Petit, Bénédicte Gérard, Bertrand Isidor, Marie-Pierre Cordier, Pascale Saugier-Veber, Gilles Morin, Gaetan Lesca, Julien Van-Gils, Bénédicte Duban-Bedu, Maude Grelet, Juliette Piard, Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Production du lait (PL), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique clinique, Hôpital Sud, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), FHU TRANSLAD, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Pontchaillou [Rennes], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Marseille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Bordeaux [Bordeaux], Institut des Sciences de la mécanique et Applications industrielles (IMSIA - UMR 9219), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint Vincent de Paul de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], International Livestock Research Institute, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Biologie Fonctionnelle, Insectes et Interactions (BF2I), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Hematology, Le CHCB, Centre Hospitalier de la Côte Basque, CHU Pitié-Salpêtrière [APHP], EDF (EDF), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Neonatal Pediatrics, Rouen University Hospital, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université catholique de Lille (UCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-EDF R&D (EDF R&D), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Hypertrichosis, Male, Pediatrics, [SDV]Life Sciences [q-bio], MESH: Magnetic Resonance Imaging, Pathognomonic, MESH: Child, Intellectual disability, MESH: Syndrome, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, biology, Wiedemann-Steiner syndrome, High-Throughput Nucleotide Sequencing, Syndrome, KMT2A, MESH: Amino Acid Substitution, Magnetic Resonance Imaging, hypertrichosis, 3. Good health, hairiness, Phenotype, Child, Preschool, cardiovascular system, Female, Disease Susceptibility, France, medicine.symptom, MESH: Tomography, X-Ray Computed, Myeloid-Lymphoid Leukemia Protein, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Disease Susceptibility, MESH: Phenotype, Short stature, MESH: Intellectual Disability, 03 medical and health sciences, Hypertrichosis cubiti, Intellectual Disability, Genetics, medicine, Humans, histone methylation, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, medicine.disease, MESH: Male, MESH: France, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, MESH: Myeloid-Lymphoid Leukemia Protein, Mutation, biology.protein, business, Tomography, X-Ray Computed, MESH: Female
Abstract

International audience; Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Published
2017
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32. Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation

Author

Rosine Guimbaud, Odile Cabaret, Julie Leclerc, Thierry Frebourg, Lucie Delattre, Tonio Lovecchio, Gilles Morin, Sophie Lejeune, Nelly Burnichon, Myriam Bronner, Emilie Ait Yahya, Pierre Laurent-Puig, Marie-Pierre Buisine, Nicole Porchet, Stéphanie Baert-Desurmont, Philippe Jonveaux, Jacques Mauillon, and Cathy Flament

Subjects
0301 basic medicine, Adult, Male, Heterozygote, Alu element, Biology, MLH1, Polymorphism, Single Nucleotide, Epigenesis, Genetic, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Promoter Regions, Genetic, Gene, Genetics (clinical), Alleles, Genetics, Intron, High-Throughput Nucleotide Sequencing, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, Introns, Pedigree, 030104 developmental biology, Haplotypes, Mutation, Mendelian inheritance, symbols, Female, MutL Protein Homolog 1
Abstract

Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far. We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations. This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5′-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription. This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.

Published
2017

33. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Author

Janine Altmüller, Stefan Böhringer, G. Eda Utine, Krystyna H. Chrzanowska, Peter Nürnberg, Maria Teresa Dotti, Marcel Martin, Holger Thiele, Johanna Christina Czeschik, Esra Kılıç, Gunnar Houge, Almuth Caliebe, Sigrid Tinschert, Koray Boduroğlu, Yun Li, Francesca Cristofoli, Filippo Beleggia, Fanny Morice-Picard, Christiane Zweier, Michèle Mathieu Dramard, Joris Vermeesch, Małgorzata Krajewska-Walasek, Beate Albrecht, Hermann-Josef Lüdecke, Ozgur Cogulu, Yasemin Alanay, Annabella Marozza, Hülya Kayserili, Timm O. Goecke, Koenraad Devriendt, Bernd Wollnik, Catheline Vilain, Pelin Ozlem Simsek-Kiper, Esther Pohl, Anita Rauch, Barbara Mikat, Michael Zeschnigk, Nursel Elcioglu, R. Vivarelli, Joussef Hayek, Alma Kuechler, Stanislas Lyonnet, Esther Milz, Dagmar Wieczorek, Sven Rahmann, Encarnación Guillén-Navarro, Blanca Gener, Ludger Klein-Hitpass, Nina Bögershausen, Gilles Morin, Ferda Ozkinay, Alessandra Renieri, Vanesa López-González, Sabine Steiner-Haldenstätt, Andreas Wollstein, Francesca Mari, İç Hastalıkları, Acibadem University Dspace, Wieczorek, Dagmar, Boegershausen, Nina, Beleggia, Filippo, Steiner-Haldenstaett, Sabine, Pohl, Esther, Li, Yun, Milz, Esther, Martin, Marcel, Thiele, Holger, Altmueller, Janine, Alanay, Yasemin, Kayserili, Hulya, Klein-Hitpass, Ludger, Bohringer, Stefan, Wollstein, Andreas, Albrecht, Beate, Boduroglu, Koray, Caliebe, Almuth, Chrzanowska, Krystyna, Cogulu, Ozgur, Cristofoli, Francesca, Czeschik, Johanna Christina, Devriendt, Koenraad, Dotti, Maria Teresa, Elcioglu, Nursel, Gener, Blanca, Goecke, Timm O., Krajewska-Walasek, Malgorzata, Guillen-Navarro, Encarnacion, Hayek, Joussef, Houge, Gunnar, Kilic, Esra, Simsek-Kiper, Pelin Ozlem, Lopez-Gonzalez, Vanesa, Kuechler, Alma, Lyonnet, Stanislas, Mari, Francesca, Marozza, Annabella, Dramard, Michele Mathieu, Mikat, Barbara, Morin, Gilles, Morice-Picard, Fanny, Ozkinay, Ferda, Rauch, Anita, Renieri, Alessandra, Tinschert, Sigrid, Utine, G. Eda, Vilain, Catheline, Vivarelli, Rossella, Zweier, Christiane, Nuernberg, Peter, Rahmann, Sven, Vermeesch, Joris, Luedecke, Hermann-Josef, Zeschnigk, Michael, Wollnik, Bernd, Ege Üniversitesi, and University of Zurich

Subjects
Male, ARID1A, 10039 Institute of Medical Genetics, Chromosomal Proteins, Non-Histone, PHF6, Medizin, Hypotrichosis, Missense mutation, Exome, FORSSMAN-LEHMANN-SYNDROME, INTELLECTUAL DISABILITY, MENTAL-RETARDATION, MUTATIONS, SWI/SNF, COMPLEX, COMPONENTS, ARID1B, SMARCB1, Child, Genetics (clinical), Sequence Deletion, Genetics, Genetics & Heredity, biology, High-Throughput Nucleotide Sequencing, General Medicine, SMARCB1 Protein, Phenotype, Chromatin, DNA-Binding Proteins, Histone, Child, Preschool, Female, Hand Deformities, Congenital, Adult, 2716 Genetics (clinical), Biochemistry & Molecular Biology, Adolescent, Foot Deformities, Congenital, Micrognathism, Mutation, Missense, 610 Medicine & health, Chromatin remodeling, 1311 Genetics, Intellectual Disability, 1312 Molecular Biology, Nucleosome, Humans, Abnormalities, Multiple, Molecular Biology, Infant, Newborn, Facies, Infant, Chromatin Assembly and Disassembly, Repressor Proteins, Face, Karyotyping, biology.protein, 570 Life sciences, Carrier Proteins, Neck, Transcription Factors
Abstract

WOS: 000327800400004, PubMed ID: 23906836, Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A, 01GM1211B]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S398]; ERARE-ANR CraniRareFrench National Research Agency (ANR); German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01GS08167]; DFGGerman Research Foundation (DFG) [BO 1955/2-3, WU 314/6-2]; Volkswagen FoundationVolkswagen [86042]; Telethon ItalyFondazione Telethon [GTB12001], This work was part of the CRANIRARE-2 Network funded by the German Federal Ministry of Education and Research (BMBF) (01GM1211A to B. W., 01GM1211B to D. W.), the TUBITAK (112S398 to H. K.) and ERARE-ANR CraniRare to S. L. This work was also funded by a grant (MRNET) from the German Federal Ministry of Education and Research (01GS08167 to D. W.), by DFG grants (BO 1955/2-3 and WU 314/6-2 to S. B. and D. W.) and by the Volkswagen Foundation (ref 86042 to A. W.). The biobank "Cell lines and DNA bank of Rett syndrome, X linked Mental Retardation and other genetic diseases", member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, provided us with specimens.

Published
2017

34. Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Author

Peter Nürnberg, Kathi Hartmann, Cordula Knopp, Didier Herent, Michèle Mathieu-Dramard, Bernard Roméo, Guillaume Jedraszak, Amrathlal Rabbind Singh, Miriam Elbracht, Nadina Ortiz Bruechle, Peter Deutz, Klaus Zerres, Yuequan Shen, Johannes Oldenburg, Dominique Brémond-Gignac, Gilles Morin, Jacques Rochette, Elisabeth Bourges-Petit, Kerstin Konrad, Halima Ouadid-Ahidouch, and Henri Sevestre

Subjects
Adult, Male, inorganic chemicals, medicine.medical_specialty, Adolescent, Migraine Disorders, Muscle Fibers, Skeletal, Erythrocytes, Abnormal, Biology, Endoplasmic Reticulum, medicine.disease_cause, Protein Structure, Secondary, Dyslexia, Calcium imaging, Internal medicine, Thrombocytopathy, Genetics, medicine, Humans, Point Mutation, Stromal Interaction Molecule 1, Allele, Child, Genetics (clinical), Aged, Calcium metabolism, Mutation, Ichthyosis, Endoplasmic reticulum, Infant, Newborn, Infant, Membrane Proteins, STIM1, Middle Aged, Miosis, medicine.disease, Neoplasm Proteins, Pedigree, Endocrinology, Child, Preschool, Muscle Fatigue, Calcium, Female, Blood Platelet Disorders, Calcium Channels, Spleen
Abstract

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910CT transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.

Published
2014
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35. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author

Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge

Subjects
Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract

Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

Published
2014

36. Delineation ofEFTUD2Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients

Author

Marie Gonzales, Alice Goldenberg, Jean-Luc Alessandri, Charles Decaestecker, Alain Verloes, Daphné Lehalle, Marie-Line Jacquemont, Marlène Rio, Muriel Holder-Espinasse, Christopher T. Gordon, Alexandre Vasiljevic, Michel Vekemans, Loïc de Pontual, Sandrine Marlin, Laurent Pasquier, Didier Lacombe, Robert Smigiel, Lucile Boutaud, Sylvie Manouvrier-Hanu, Valérie Malan, Arnold Munnich, Jeanne Amiel, Stanislas Lyonnet, Christel Thauvin-Robinet, Roseline Caumes, Geneviève Baujat, Odile Boute-Benejean, Florence Petit, Myriam Oufadem, Gilles Morin, Neus Baena, Clarisse Baumann, Dominique Gaillard, Tania Attié-Bitach, Géraldine Goudefroye, and Michèle Mathieu-Dramard

Subjects
Male, Pediatrics, medicine.medical_specialty, Microcephaly, Hearing loss, Haploinsufficiency, Disease, Choanal atresia, Biology, Anus, Imperforate, Diagnosis, Differential, Hearing Loss, Bilateral, Pregnancy, Intellectual Disability, Prenatal Diagnosis, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Ear, External, Child, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Ophthalmoplegia, Infant, Peptide Elongation Factors, medicine.disease, External ear malformation, Thrombocytopenia, Phenotype, Child, Preschool, Atresia, Mutation, Female, medicine.symptom, Hand Deformities, Congenital, Mandibulofacial Dysostosis
Abstract

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

Published
2014
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37. Le Comit� ouvrier de secours imm�diat, ��une entreprise allemande sous le masque de la solidarit頻

Author

Gilles Morin

Subjects
General Medicine
Abstract

Des syndicalistes fondent en mars 1942, apres les bombardements anglais des usines Renault, un organisme humanitaire sous l’egide des nazis. Ceux-ci financent genereusement jusqu’en 1945 cet organisme collaborationniste pluraliste domine par le Rassemblement national populaire (RNP) et le Parti populaire francais (PPF), au moyen d’une amende sur les « fortunes juives ». Pare a la fois de la tradition ouvriere et de l’action l’humanitaire, le Comite ouvrier de secours immediat (COSI) fustige sans relâche les « crimes anglo-saxons », etale la generosite allemande et contourne le Secours national vichyste. Par-dela une aide concrete aux victimes des raids allies qui se multiplient, le COSI s’avere un lieu majeur de corruption du syndicalisme que l’epuration frappera peu.

Published
2019
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38. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Author

Anne-Marie Guerrot, Joelle Roume, Thierry Frebourg, Patricia Faure, Pascale Saugier-Veber, Sylvain Renolleau, Séverine Audebert-Bellanger, Gilles Morin, Isabelle Desguerre, Renaud Touraine, Ghislaine Plessis, Séverine Drunat, Marjolaine Willems, Sarah Grotto, Hubert Journel, Eric Verspyck, Brigitte Simon-Bouy, Jean-Marie Cuisset, Anne-Gaëlle Grebille, Stéphane Marret, Vincent Flurin, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de neurologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Centre Hospitalier de Versailles André Mignot (CHV), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Service de gynécologie et obstétrique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Heart Defects, Congenital, Male, 0301 basic medicine, Weakness, Pediatrics, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], SMN1, Spinal Muscular Atrophies of Childhood, Ultrasonography, Prenatal, 03 medical and health sciences, Life Expectancy, 0302 clinical medicine, medicine, Humans, Increased nuchal translucency, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Respiratory Distress Syndrome, Newborn, Pregnancy, Reflex, Abnormal, business.industry, Homozygote, Infant, Newborn, Muscle weakness, Spinal muscular atrophy, medicine.disease, SMA, Survival of Motor Neuron 1 Protein, Cranial Nerve Diseases, Hypotonia, 3. Good health, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Autonomic Nervous System Diseases, Neurology, Muscle Hypotonia, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Results Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

Published
2016
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40. Les socialistes français à l’heure de la Libération. Perspectives française et européenne

Author

Castagnez, Noëlline, Cépède, Frédéric, Gilles, Morin, Ollivier, Anne-Laure, Centre d'histoire de Sciences Po (CHSP), Sciences Po (Sciences Po), Centre d'études politiques contemporaines (CEPOC), Pouvoirs - Lettres - Normes (POLEN), Université d'Orléans (UO)-Université d'Orléans (UO), Centre d'histoire sociale des mondes contemporains (CHS), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), and Centre d'histoire de Sciences Po (Sciences Po) (CHSP)

Subjects
[SHS.HIST]Humanities and Social Sciences/History, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

41. Quelle prise en charge pour les hommes asymptomatiques, porteurs d’une mutation du gène BRCA1 ou 2 ? Résultat d’une enquête de pratique auprès des centres d’oncogénétique français

Author

Gilles Morin, Claire Gillaux, Michèle Mathieu, Jean Gondry, Bénédicte Demeer, Iglika Brachot-Simeonova, and Raffaèle Fauvet

Subjects
Gynecology, Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Physical examination, Hematology, General Medicine, Guideline, medicine.disease, Asymptomatic, Prostate-specific antigen, Prostate cancer, Breast cancer, Oncology, Pancreatic cancer, Mutation (genetic algorithm), medicine, Radiology, Nuclear Medicine and imaging, medicine.symptom, business
Abstract

The aim of this survey of practice was to define, in the absence of guideline, the management in France of asymptomatic men bearing a mutation of BRCA1 or 2 genes. A questionnaire was addressed to 90 oncogenetics centers. We obtained the answers of 34 practitioners working in 58 centers. Among the responders, 85.3% offered a systematic genetic test in all cases to determine the risk of transmission to the children and to offer a personal follow-up in 79.4 % of cases. This screening was directed towards prostate cancer, breast cancer and pancreatic cancer in respectively 94.1, 67.6 and 47.1% of cases. The screening of prostate cancer was mainly proposed to men bearing a BRCA2 mutation and from the age of 40 years. It was based on clinical examination and testing of prostate specific antigen. The screening of breast cancer was mainly proposed to men bearing a BRCA2 mutation and based on clinical examination and self-palpation without stating a started age. The screening of pancreatic cancer was mainly proposed to men with familial history of pancreatic cancer and from the age of 40 years. It was based on tomography and MRI. For the majority of answerers, the general practitioner was the best to perform all these screenings. These experts' opinions can help to establish guidelines for the global management of asymptomatic men carriers of BRCA1 or 2 mutations.

Published
2012
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42. SETD5 haploinsufficiency phenotypic refinement: Expanding the range of chromatin disorders

Author

Nicolas Chatron, Jeanne Amiel, Hubert Journel, Gilles Morin, Gaetan Lesca, Valérie Malan, Julien Thevenon, David Geneviève, Anne Claude Tabet, Anneleen Boogaerts, Marie Vincent, Sébastien Moutton, Laurence Olivier-Faivre, Marlène Rio, Sophie Naudion, Marianne Till, Damien Sanlaville, Anna C.E. Hurst, Bertrand Isidor, and Eulalie Lasseaux

Subjects
Genetics, Range (biology), Pediatrics, Perinatology and Child Health, Neurology (clinical), General Medicine, Biology, Haploinsufficiency, Phenotype, Chromatin
Published
2017
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43. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Author

Patrick Niaudet, François Nobili, Guylhène Bourdat-Michel, Estelle Colin, Karin Dahan, Brigitte Gilbert-Dussardier, Claire Rigothier, Robert Novo, Dominique Martin-Coignard, Justine Bacchetta, Karim Bouchireb, Rémi Salomon, Thierry Hannedouche, Ariela Vergara-Jaque, Chantal Loirat, Dominique Chauveau, Pascal Houillier, Stéphane Burtey, Nicole Van Regemorter, Lamisse Mansour-Hendili, Sandrine Lemoine, Xavier Jeunemaitre, Muriel Holder-Espinasse, Michel Fischbach, Denis Morin, François-Guillaume Debray, S. Benoit, Valérie Leroy, Gilles Morin, Marie Alice Macher, Andreas Schleich, Mathilde Cailliez, Hassan Izzedine, Isabelle Roncelin, Gwenaëlle Roussey-Kesler, Cyrielle Treard, Claire Cartery, Hubert Nivet, Stéphane Lourdel, Véronique Baudouin, Pierre Cochat, Bertrand Knebelmann, Anne Blanchard, Wendy González, Estelle Desport, Tim Ulinski, Stella Dieguez, Marco Janner, Rosa Vargas-Poussou, Laurence Faivre, Alexandre Karras, Nelly Le Pottier, Francesco Emma, Philippe Vanhille, Renaud de la Faille, Anne Laure Sellier-Leclerc, J. Fourcade, Olivier Devuyst, Denis Fouque, Kenza Soulami, Aurélien Tiple, Etienne Bérard, Laurenne Dehoux, Marie Pierre Lavocat, Hélène François, Gérard Champion, Gerard Cardon, Georges Deschênes, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Univ Talca, Escuela Ingn Bioinfomat, Talca, Chile, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies rénales rares Néphrogones [CHU-HCL, Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice)-Fondation LENVAL-Hopital pour Enfants, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité de Néphrologie Pédiatrique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Division of Nephrology, Université catholique de Louvain Medical school, Université Catholique de Louvain = Catholic University of Louvain (UCL), Department of Nephrology and Urology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma]-IRCCS, Service de Néphrologie pédiatrique [Hôpital de Hautepierre, Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Human-machine spoken dialogue (CORDIAL), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Institut National de Recherche en Informatique et en Automatique (Inria)-École Nationale Supérieure des Sciences Appliquées et de Technologie (ENSSAT), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service de Physiologie [Georges-Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de Néphrologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de néphrologie adultes [CHU Necker], Sciences pour l'environnement (SPE), Centre National de la Recherche Scientifique (CNRS)-Université Pascal Paoli (UPP), Service de néphrologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Métal, Travaux et recherches archéologiques sur les cultures, les espaces et les sociétés (TRACES), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie, Hôpital de Clocheville, Service de néphrologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unité Néphrologie Pédiatrique [CHRU Lille], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Nephrology, Transplantation and Dialysis, Bordeaux, Hospices Civils de Lyon (HCL), Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd [Casablanca], CHU Clermont-Ferrand, Service de néphrologie et pédiatrie générale [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine interne et néphrologie, CH Valenciennes, Centre de Génétique de Bruxelles, Université libre de Bruxelles (ULB), Service de Génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Ministry of Health (Plan Maladies Rares), European Community FP7EUNEFRON 201590 and EURenOmics 2012‐305608, The Chilean PIA‐Conycit program (grant ACT‐1104), The Swiss National Science Foundation project (grant 310030_146490), RADIZ, Rare Diseases Initiative Zürich, a KFSP of the University of Zurich., Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Médecine interne et immunopathologie clinique [CHU Toulouse], Pôle IUCT [CHU Toulouse], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Université Pascal Paoli (UPP)-Centre National de la Recherche Scientifique (CNRS), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Université Catholique de Louvain (UCL), IRCCS-IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de nephrologie pédiatrique, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]-Sorbonne Université (SU), Free University of Brussels (BELGIUM), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Néphrologie, Centre Hospitalier Universitaire (CHU), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, chloride channel, renal failure, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Dent Disease, ClC-5, medicine.disease_cause, Cohort Studies, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, low molecular weight proteinuria, Genetics (clinical), Genetics, Mice, Knockout, 0303 health sciences, Mutation, biology, MESH: Genetic Predisposition to Disease, MESH: Anion Transport Proteins, Phenotype, 3. Good health, Pedigree, Chloride Channels/chemistry/*genetics/metabolism, Dent Disease/*genetics/metabolism, Nephrocalcinosis, MESH: Bartter Syndrome, MESH: Mutation, Knockout, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Tubulopathy, Chloride Channels, medicine, Animals, Humans, Genetic Association Studies, 030304 developmental biology, MESH: Humans, CLCN5, MESH: Chloride Channels, Dent disease 1, medicine.disease, Bartter syndrome, biology.protein, OCRL, CLC family of chloride transporters and channels
Abstract

International audience; Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

Published
2015
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44. Le congrès de 1967 du PSU: M. Rocard au pouvoir

Author

Jalabert, Laurent, Castagnez, Noëlline, Lazar, Marc, Gilles, Morin, Sirinelli, Jean-François, Identités, Territoires, Expressions, Mobilités (ITEM), Université de Pau et des Pays de l'Adour (UPPA), Centre d'histoire de Sciences Po (Sciences Po) (CHSP), Sciences Po (Sciences Po), Noëlline Castagnez, Laurent Jalabert, Marc Lazar, Gilles Morin, Jean-François Sirinelli, and Centre d'histoire de Sciences Po (CHSP)

Subjects
Parti socialiste, Histoire politique, France, Socialisme, [SHS.HIST]Humanities and Social Sciences/History, ComputingMilieux_MISCELLANEOUS, [SHS.SCIPO]Humanities and Social Sciences/Political science
Abstract

International audience

Published
2013

45. 15q11.2 microdeletion (BP1–BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients

Author

Marie-Christine Vantyghem, Delphine Fauvert, Bénédicte Duban, Florence Petit, Frenny Sheth, Roseline Caumes, Louis Vallée, Valérie Malan, Guillaume Jedraszak, Jean-Marie Cuisset, Odile Boute, Patricia Blanchet, Valérie Cormier-Daire, Matthieu Decamp, Marie Pigeyre, Marion Gérard, Joelle Roume, Sandrine Lanco-Dosen, Nathalie Lemeur, Pierre Sarda, Muriel Holder-Espinasse, Jacques Puechberty, Frédéric Bilan, Gilles Morin, Lucie Pinson, David Geneviève, Ghislaine Plessis, Bruno Delobel, Marie-Pierre Lemaitre, Sylvie Manouvrier-Hanu, Clémence Vanlerberghe, Brigitte Gilbert-Dussardier, Sonia Bouquillon, Joris Andrieux, Catherine Vincent-Delorme, Michèle Mathieu, Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique clinique (CHU Lille), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Guy's Hospital [London], Hôpital Saint-Vincent de Paul, Service de Neuro-pédiatrie[Lille], Hôpital Claude Huriez [Lille], CHU Lille, CHR Sambre-Avesnois, Institut Lillois d'Ingénierie de la Santé (ILIS), Université de Lille, Droit et Santé-Université de Lille, Droit et Santé, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Amiens-Picardie, Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], CHI Poissy-Saint-Germain, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), CHU Rouen, Normandie Université (NU), Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Pediatrics, Heart disease, Developmental Disabilities, Aneuploidy, 15q11.2 microdeletion, Cohort Studies, Epilepsy, 0302 clinical medicine, Copy-number variation, Child, Cation Transport Proteins, Genetics (clinical), In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Comparative Genomic Hybridization, Mental Disorders, General Medicine, Middle Aged, Penetrance, 3. Good health, Phenotype, Child, Preschool, Cohort, Female, Chromosome Deletion, Microtubule-Associated Proteins, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Heart Diseases, NIPA2, NIPA1, Speech Disorders, CYFIP1, 03 medical and health sciences, Chromosome 15, Young Adult, BP1–BP2, Intellectual Disability, TUBGCP5, medicine, Humans, Generalized epilepsy, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Congenital heart disease, Chromosome Aberrations, Chromosomes, Human, Pair 15, business.industry, Infant, Membrane Proteins, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, business, 030217 neurology & neurosurgery
Abstract

International audience; Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Published
2015
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46. Baraitser-Winter cerebrofrontofacial syndrome : Delineation of the spectrum in 42 cases

Author

Sara Osimani, Andrew E. Fry, Koenraad Devriendt, Débora Romeo Bertola, Marjan M. Nezarati, Han G. Brunner, Grazia M.S. Mancini, Jorge L. Juncos, Pirayeh Eftekhari, Nataliya Di Donato, Marjolijn C.J. Jongmans, Laurence Faivre, Gilles Morin, Małgorzata J.M. Nowaczyk, Didier Lacombe, Zeichi-Seide Roseli, Conny M. A. van Ravenswaaij, Daniela Melis, Julien Masliah-Planchon, William B. Dobyns, Alexander Hoischen, Hatice Koçak Eker, Marlies Kempers, Andreas Rump, Vera Uliana, Victoria Mok Siu, Fabienne Giuliano, Nicole Philip, Beate Albrecht, Omar A Abdul-Raman, Alain Verloes, Mirjam Klaus, Angela E. Lin, Massimiliano Rossi, Albert David, Bregje W.M. van Bon, Jeanette C. Ramer, Ludivine Templin, Séverine Drunat, Yves Sznajer, Vincent Procaccio, Jean-Baptiste Rivière, Mary Ella M Pierpont, Francesca Faravelli, Judith Allanson, Leina Guion Almeida, Daniela T. Pilz, Cristina Rusu, Nicolas Chassaing, Charles Marques Lourenço, Bruce H. Wainer, Valérie Drouin-Garraud, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universitätsklinikum Carl Gustav Carus, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Mississippi Medical Center (UMMC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Children's Hospital of Eastern Ontario [Ottawa, Canada], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital Gasthuisberg, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rouen, Normandie Université (NU), Ospedale Galliera, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nice (CHU Nice), University of São Paulo (USP), Emory University School of Medicine, Emory University [Atlanta, GA], CHU Bordeaux [Bordeaux], Massachusetts General Hospital [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli studi di Napoli Federico II, University of Western Ontario (UWO), CHU Amiens-Picardie, McMaster University [Hamilton, Ontario], Pennsylvania State University (Penn State), Penn State System, Hôpital de la Timone [CHU - APHM] (TIMONE), University of Minnesota [MN, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], University Hospital Groningen, University Hospital of Wales [Cardiff, UK], Seattle Children’s Hospital, Clinical Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Ethical, Legal, Social Issues in Genetics (ELSI), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Microcephaly, Pathology, Craniofacial abnormality, [SDV]Life Sciences [q-bio], Medizin, GYRAL MALFORMATIONS, Craniofacial Abnormalities, FUNCTIONAL DIVERSITY, 0302 clinical medicine, Ptosis, Gene Order, Genetics(clinical), Hypertelorism, Non-U.S. Gov't, Child, Genetics (clinical), Arthrogryposis, Dystonia, 0303 health sciences, Research Support, Non-U.S. Gov't, Anatomy, 3. Good health, Phenotype, Child, Preschool, Female, medicine.symptom, Abnormalities, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, APPARENTLY UNDESCRIBED SYNDROME, Adolescent, Lissencephaly, Biology, Research Support, Article, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Abnormalities, Multiple, Preschool, 030304 developmental biology, SHALLOW ORBITS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], GAMMA-ACTIN, Pachygyria, Facies, medicine.disease, IRIS COLOBOMA, Actins, BETA-ACTIN, Amino Acid Substitution, Genetic Loci, Mutation, FACIAL SYNDROME, 030217 neurology & neurosurgery, MENTAL-RETARDATION, GROWTH-RETARDATION
Abstract

International audience; Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.

Published
2015
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47. Stormorken syndrome or York platelet syndrome: A clinician's dilemma

Author

Gilles Morin, Jacques Rochette, and Amrathlal Rabbind Singh

Subjects
Miosis, lcsh:R5-920, Pediatrics, medicine.medical_specialty, Pathology, business.industry, York platelet syndrome, YORK PLATELET SYNDROME, Dilemma, Endocrinology, lcsh:Biology (General), STORMORKEN SYNDROME, Genetics, medicine, medicine.symptom, lcsh:Medicine (General), business, lcsh:QH301-705.5, Molecular Biology, Letter to the Editor, Tubular aggregate myopathy, Stormorken syndrome
Published
2015

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