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51. A framework to identify modifier genes in patients with Phelan-McDermid syndrome

Author: Séverine Drunat, Frédérique Amsellem, Dominique Martin, Laurence Faivre, Sandra Chantot-Bastaraud, Bertrand Isidor, James Lespinasse, Sandrine Passemard, Jean Chiesa, Roberto Toro, Olivier Pichon, Françoise Devillard, Céline Dupont, Damien Haye, Julien Buratti, Hubert Journel, Sandra Whalen, Marie Ducloy, Cédric Le Caignec, Thomas Rolland, Alexandre Mathieu, Jean-Michel Dupont, Marie-Laure Vuillaume, Annick Toutain, Alain Verloes, Delphine Héron, Didier Lacombe, Jonathan M. Levy, Nicole Philip, Damien Sanlaville, Laurence Perrin, Anne-Claude Tabet, Laetitia Gouas, Caroline Rooryck, Mélanie Fradin, Richard Delorme, Philippe Vago, Christèle Dubourg, Eva Pipiras, Klaus Dieterich, Vincent Gatinois, Claire Beneteau, Jacques Puechberty, Thomas Bourgeron, Véronique Satre, Aurélia Jacquette, Lucile Pinson, Boris Keren, Albert David, Brigitte Benzacken, Anne-Laure Mosca-Boidron, Cyril Mignot, Charles Coutton, Patrick Edery, Chantal Missirian, Chloé Quélin, Alexandra Afenjar, Yline Capri, Stephan Kemeny, Abdelamdjid Benmansour, and Isabelle Marey
Subjects: Genetics, 0303 health sciences, Locus (genetics), Biology, medicine.disease, Corpus callosum, Major gene, SHANK3 Gene, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Autism, In patient, 030217 neurology & neurosurgery, 030304 developmental biology, Modifier Genes
Abstract: Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
Published: 2017

52. 'Lowe syndrome: A particularly severe phenotype without clinical kidney involvement'

Author: Klaus Dieterich, Ahmed A. ElBeheiry, Julien Fauré, Julien Thevenon, John Rendu, and Ebtesam M. Abdalla
Subjects: 0301 basic medicine, Adult, Male, Oculocerebrorenal syndrome, Central nervous system, 030232 urology & nephrology, Bioinformatics, Kidney, Cataract, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Catalytic Domain, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), business.industry, Glaucoma, medicine.disease, Phenotype, Pathophysiology, Phosphoric Monoester Hydrolases, 030104 developmental biology, medicine.anatomical_structure, Oculocerebrorenal Syndrome, Mutation, OCRL, Egypt, Psychomotor Disorders, Psychomotor disorder, business, Kidney disease
Abstract: Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23-year-old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.
Published: 2017

53. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Anne-Claude Tabet, Thomas Rolland, Marie Ducloy, Jonathan Lévy, Julien Buratti, Alexandre Mathieu, Damien Haye, Laurence Perrin, Céline Dupont, Sandrine Passemard, Yline Capri, Alain Verloes, Séverine Drunat, Boris Keren, Cyril Mignot, Isabelle Marey, Aurélia Jacquette, Sandra Whalen, Eva Pipiras, Brigitte Benzacken, Sandra Chantot-Bastaraud, Alexandra Afenjar, Delphine Héron, Cédric Le Caignec, Claire Beneteau, Olivier Pichon, Bertrand Isidor, Albert David, Laila El Khattabi, Stephan Kemeny, Laetitia Gouas, Philippe Vago, Anne-Laure Mosca-Boidron, Laurence Faivre, Chantal Missirian, Nicole Philip, Damien Sanlaville, Patrick Edery, Véronique Satre, Charles Coutton, Françoise Devillard, Klaus Dieterich, Marie-Laure Vuillaume, Caroline Rooryck, Didier Lacombe, Lucile Pinson, Vincent Gatinois, Jacques Puechberty, Jean Chiesa, James Lespinasse, Christèle Dubourg, Chloé Quelin, Mélanie Fradin, Hubert Journel, Annick Toutain, Dominique Martin, Abdelamdjid Benmansour, Claire S. Leblond, Roberto Toro, Frédérique Amsellem, Richard Delorme, Thomas Bourgeron, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Dijon, Département de génétique médicale [Hôpital de la Timone - APHM], 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), Hospices Civils de Lyon (HCL), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Métropole Savoie [Chambéry], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Hôpital Chubert, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the FondaMental Foundation, the GenMed Labex and the BioPsy Labex. The research leading to these results has received funding from the ERA-Net NEURON Cofund Programme under 'Horizon 2020' (SynPathy project), the ANR SynDivAutism, the Human Brain Project, and from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution., We are grateful to the families for participating in this study. We thank Isabelle Cloëz-Tayarani, Ksenia Bagrintseva and Gaël Millot for helpful discussions and careful reading of the manuscript. This study was funded by a French partnership between the Clinical Research Department of the AP-HP Institution and the Institut Pasteur. It was also supported by the PMS French association (Mrs Meunier), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), European Project: 291840,EC:FP7:HEALTH,FP7-ERANET-2011-RTD,ERA-NET NEURON II(2012), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (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), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], CHU de Lyon, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier de Chambéry (C.H.de Chambéry), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Herrada, Anthony, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Network of European funding for Neuroscience research - ERA-NET NEURON II - - EC:FP7:HEALTH2012-01-01 - 2015-12-31 - 291840 - VALID, European Autism Interventions - A Multicentre Study for Developing New Medications - EU-AIMS - - EC:FP7:SP1-JTI2012-04-01 - 2017-03-31 - 115300 - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Genetics, lcsh:QH426-470, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:R, Neurodevelopmental disorders, lcsh:Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Clinical genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract: International audience; Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes theSHANK3gene.SHANK3is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inheritedSHANK3deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
Published: 2017

54. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Author: Marjon van Slegtenhorst, Jean-Louis Mandel, Paul R. Mark, Jane Juusola, Gretchen Von Allmen, Elise Schaefer, Aurora Pujol, Grazia M.S. Mancini, Francesca Mattioli, Gaëlle Vieville, Marielle Alders, Mark Engelen, Charles Coutton, Klaus Dieterich, Alex Magee, Jan Maarten Cobben, Amélie Piton, 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de génétique médicale d’Alsace, Belfast City Hospital, Spectrum Health [Grand Rapids], Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Grenoble Alpes - Site NORD [La Tronche], hôpital couple-enfant [CHU Grenoble Alpes], McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut Albert Bonniot, GeneDx [Gaithersburg, MD, USA], Catalan Institution for Research & Advanced Studies [Barcelona, Catalonia, Spain] (ICREA), ARD - Amsterdam Reproduction and Development, Human Genetics, ANS - Cellular & Molecular Mechanisms, Paediatric Genetics, ACS - Pulmonary hypertension & thrombosis, and Clinical Genetics
Subjects: 0301 basic medicine, Adult, Male, Haploinsufficiency, Biology, Blepharophimosis, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, Report, Intellectual Disability, Genetics, medicine, Blepharoptosis, Humans, Child, Frameshift Mutation, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Genes, Dominant, Histone Acetyltransferases, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Point mutation, Nuclear Proteins, Acetylation, Methyltransferases, Syndrome, medicine.disease, Molecular biology, Hypotonia, DNA-Binding Proteins, 030104 developmental biology, Phenotype, Child, Preschool, Muscle Hypotonia, Female, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion
Abstract: Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs(∗)8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
Published: 2017

55. Delineation of the 3p14.1p13 microdeletion associated with syndromic distal limb contractures

Author: Michel Francoise, Patrick Callier, Steven A. Vokes, Susanne Kjaergaard, Laurence Duplomb, Thomas Lee Dahm, Julien Thevenon, Nicole Monnier, Marie Hélène Aubriot-Lorton, Frédéric Huet, Tara Montgomery, Haley O. Tucker, Clémence Ragon, Nathalie Marle, Katherine Neas, Francine Mugneret, Pierre-Simon Jouk, Joël Lunardi, Klaus Dieterich, Laurence Faivre, Christel Thauvin-Robinet, Anne Laure Mosca-Boidron, Joanne Dixon, 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 ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Laboratoire de cytogénétique (CHU de Dijon), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Service de pédiatrie, Centre Hospitalier Wiliam Morey, Northern Genetics Service, Newcastle University [Newcastle], Department of Clinical Genetic, Rigshospitalet [Copenhagen], Central and Southern Regional Genetic Services, Wellington Hospital Private, Department of Pediatrics, Nordsjællands Hospital - Hillerød, Service de pédiatrie (CHU de Dijon), Service de Pathologie [CHU de Dijon], Section of Molecular Cell & Developmental Biology, Institute for Cellular and Molecular Biology-University of Texas at Austin [Austin], Graduate Program in Cell and Molecular Biology, University of Texas at Austin [Austin], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Chalon-sur-Saône William Morey, Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, University of Texas at Austin [Austin]- Institute for Cellular and Molecular Biology, and Roux-Buisson, Nathalie
Subjects: Male, Pathology, medicine.medical_specialty, Contracture, [SDV]Life Sciences [q-bio], Locus (genetics), FOXP1, Biology, Mice, distal limb contractures, symbols.namesake, Exon, EIF4E3, Intellectual disability, Genetics, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 3p141p13 microdeletion, Genetics (clinical), Arthrogryposis, Chromosome Aberrations, Mice, Knockout, Sanger sequencing, Comparative Genomic Hybridization, [ SDV ] Life Sciences [q-bio], Extremities, Forkhead Transcription Factors, Syndrome, Microdeletion syndrome, medicine.disease, Blepharophimosis, Phenotype, Repressor Proteins, [SDV] Life Sciences [q-bio], array-CGH, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], symbols, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chromosomes, Human, Pair 3, France, Carrier Proteins, intronic regulatory sequence
Abstract: International audience; Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20–25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 micro-deletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.
Published: 2014

56. Prevalence and characteristics of children with mild intellectual disability in a French county

Author: Christine Cans, M. David, Klaus Dieterich, J. Bloch, Pierre-Simon Jouk, J. Counillon, A. Billette de Villemeur, and B. Larroque
Subjects: medicine.medical_specialty, Intelligence quotient, business.industry, Incidence (epidemiology), Public health, Rehabilitation, Prevalence, medicine.disease, Comorbidity, Psychiatry and Mental health, Neurology, Arts and Humanities (miscellaneous), Intellectual disability, medicine, International Statistical Classification of Diseases and Related Health Problems, Neurology (clinical), Psychiatry, business, Socioeconomic status, Demography
Abstract: Background Studies conducted on mild intellectual disability (MID) in children are infrequent and the prevalence rates vary widely. This study aimed to estimate the prevalence of MID in children in a French county (Isere), to describe the clinical signs and associated comorbidities, and to specify the aetiologies of this disability. Methods The target population was comprised of the 15 100 children born in 1997 residing in Isere County, France, in 2008. Our goal was to find the children in this group with MID diagnosed between 9 and 13 years of age. MID was defined as an overall IQ score of between 50 and 69 [International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)]; this definition was adjusted for the study by integrating confidence intervals so that the risk of IQ measurement relativity and possible discrepancy of scores could be taken into account. Children were identified through an administrative data source designed to assist disabled persons that contains health information, and an educational data source. Parents who agreed to let their children participate responded to an in-depth questionnaire on their child's medical and academic history. A genetic investigation was proposed for those children whose MID had an unknown aetiology. Results The preliminary selection included 267 children, resulting in a prevalence rate of 18 per 1000 (CI [15.6; 19.9]), within the expected mean. Of these 267 cases, 181 families agreed to participate in the study (68%). MID more often affected boys [male gender ratio = 1.4 (CI [1.2; 1.6])], low socioeconomic groups, and families with a history of intellectual disability. The clinical signs and comorbidities associated with MID were very frequent, with 54% spoken language disorders and 10% pervasive developmental disorder. Only 9% of the children had undergone a genetic investigation before the study. The known aetiology rate for MID was 19% among all the children who had had genetic tests performed. Conclusion MID is an important public health issue based on its prevalence. The associated clinical signs and comorbidities may be warning signs of MID in case of learning difficulties. This study may help decision-makers to develop and organise screening and care for MID.
Published: 2013

57. Handicap in adults with arthrogryposis is severe, partly invisible and varies by genotype

Author: Pierre-Simon Jouk, Bernard Wuyam, Shenhao Dai, Dominic Pérennou, Klaus Dieterich, and Marie Jaeger
Subjects: musculoskeletal diseases, Arthrogryposis, Amyoplasia, Pediatrics, medicine.medical_specialty, Arthrogryposis multiplex congenita, business.industry, Rehabilitation, Muscle weakness, medicine.disease, International Classification of Functioning, Disability and Health, Cohort, medicine, Anxiety, Orthopedics and Sports Medicine, Respiratory function, medicine.symptom, business
Abstract: Introduction/Background To understand the nature of the handicap of adults with arthrogryposis multiplex congenita (AMC), a rare disease spectrum characterized by at least two joint contractures at birth in different body areas, and analyze its possible variation by genotypes. Material and method Retrospective analysis of data for unselected persons with AMC referred to the French center for adults with AMC from 2010 to 2016. All underwent a pluri-professional systematic and comprehensive investigation of deficits, activity limitation, and participation restriction according to the International Classification of Functioning, Disability and Health and genetic analysis when indicated. Participants were divided by Amyoplasia and other AMC types. Results Mean (SD) age of the 43 participants (27 females) was 33.2 (13.4) years; 28 had Amyoplasia and 15 other types of AMC. Beyond joint stiffness, deformities and muscle weakness, the well-known core symptoms that we quantified and for which first-line treatment involved technical aids for 50% (wheelchair for 35%, electrical wheelchair 28%, manual wheelchair 7%, crutches or orthopedic shoes 14%) and human aid for 40%, requiring technical aids more frequent with Amyoplasia than other AMC types (61% vs. 27%, P = 0.05). Other less visible disorders that could contribute to severe participation restriction were particularly pain (91%) and psychological problems including anxiety, fatigue, difficulty in sexual life, altered self-esteem, and feelings of solitude. Severe respiratory disorders were infrequent and were linked to PIEZO2 mutations (only in other AMC types), respiratory function was better with Amyoplasia than other AMC types (FVC 3.8 [3–4.3] vs. 2.2 [1.4–2.7], P Conclusion This study describes disability patterns of a cohort of adults with AMC by genotype. The handicap of adults with AMC is influenced by genotype, with an important invisible handicap.
Published: 2018

58. Brachytelephalangic Chondrodysplasia Punctata: Prenatal Diagnosis and Postnatal Outcome

Author: Stéphanie Boulet, Pierre-Simon Jouk, Claudia Durand, Catherine Charra, Marc Althuser, Klaus Dieterich, Jean-Patrick Schaal, Frédérique Nugues, Maternité, Hôpital Chambéry, Clinique de génétique, CHU Grenoble, Centre de diagnostic prénatal, Gynécologue - Obstétricien, Médecin libéral, Clinic of Gynecology and Obstetrics, University Hospital, Grenoble, France, and Roux-Buisson, Nathalie
Subjects: Male, Embryology, Pathology, MESH: Maxilla, MESH: Amniocentesis, MESH: Pregnancy, Pregnancy, Binder phenotype, Prenatal Diagnosis, Maxilla, Chondrodysplasia punctata, Maxillofacial Development, Arylsulfatase E, Arylsulfatases, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Pregnancy Outcome, MESH: Nose, MESH: Ultrasonography, Prenatal, Obstetrics and Gynecology, Genetic Diseases, X-Linked, General Medicine, MESH: Maxillofacial Abnormalities, Hypoplasia, Maxillofacial Abnormalities, 3. Good health, Bone dysplasia, Amniocentesis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Face, musculoskeletal diseases, Chondrodysplasia Punctata, medicine.medical_specialty, Mutation, Missense, Prenatal diagnosis, Nose, Ultrasonography, Prenatal, Brachytelephalangy, 03 medical and health sciences, Peroxisomal disorder, MESH: Genetic Diseases, X-Linked, medicine, Humans, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neonatology, MESH: Prenatal Diagnosis, MESH: Arylsulfatases, MESH: Maxillofacial Development, 030304 developmental biology, MESH: Mutation, Missense, MESH: Humans, business.industry, Epiphyseal stippling, MESH: Pregnancy Outcome, medicine.disease, MESH: Chondrodysplasia Punctata, Osteochondrodysplasia, MESH: Male, Face, Pediatrics, Perinatology and Child Health, business, MESH: Female
Abstract: International audience; We report the prenatal management of a brachytelephalangic chondrodysplasia punctata (CDPX1) case and how postnatal findings confirmed the diagnosis. The mother was initially referred after ultrasound revealed an abnormal fetal mid-face and punctuation of upper femoral epiphyses. Chondrodysplasia punctata (CP) with Binder anomaly was suspected. 3D-HCT revealed brachytelephalangy suggesting CDPX1. At birth, mid-face hypoplasia was marked. Postnatal imaging and genetic analysis confirmed the initial diagnosis. Binder anomaly is probably always associated with CP. The newly revised CP classification facilitates the diagnosis. The main etiologies are metabolic and chromosomal abnormalities, and arylsulfatase E enzyme dysfunction. Thus, screening for arylsulfatase E mutation is mandatory for an accurate diagnosis and can lead to better delineation among CP etiologies associated with a Binder phenotype.
Published: 2010

59. Rôle d’aurora kinase C (AURKC) dans la reproduction humaine

Author: Sylviane Hennebicq, Yorgos Nikas, Raoudha Zouari, Radu Harbuz, Klaus Dieterich, Joël Lunardi, and Pierre F. Ray
Subjects: Infertility, Genetics, 0303 health sciences, Mutation, education.field_of_study, 030219 obstetrics & reproductive medicine, Genetic heterogeneity, Population, Obstetrics and Gynecology, General Medicine, Biology, Disease gene identification, medicine.disease, medicine.disease_cause, Phenotype, 3. Good health, Male infertility, 03 medical and health sciences, 0302 clinical medicine, Reproductive Medicine, medicine, education, Gene, 030304 developmental biology
Abstract: Infertility concerns at least 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. Hundreds of genes are probably involved in spermatogenesis and oogenesis and this genetic heterogeneity has so far hindered the identification of genes causing infertility in the human. Careful morphological examination of spermatozoa can provide cues to identify homogeneous cohorts of patients likely to have the same genetic defect. We studied a cohort of North-Africans patients with a rare phenotype of large-headed spermatozoa. Using a homozygosity mapping strategy, we could map the morbid gene and we identified the same homozygous mutation (c.144delC) in the aurora kinase C gene (AURKC) of all patients studied initially. We then genotyped a total of 62 patients. All who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n=34), whereas no AURKC mutations were detected in the others. A carrier frequency of 1/50 was established from individuals from the Maghrebian population, indicating that 1 in 10,000 men from North-African can be expected to present this form of infertility, a frequency comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. Then we demonstrated by flow cytometry that all spermatozoa have in fact a homogeneous 4C. We recommend the realisation of a molecular diagnosis to all patients with large-headed spermatozoa. ICSI is formally contraindicated for all homozygous patients who can have recourse to donor sperm or adoption. One cannot be as categorical for the patients not harbouring an AURKC mutation.
Published: 2009

60. 13q31.1 microdeletion: A prenatal case report with macrocephaly and macroglossia

Author: Pierre-Simon Jouk, Virginie Guigue, Brice Poreau, Klaus Dieterich, Candice Ronin, Stéphanie Lin, Sophie Brouillet, Charles Coutton, Véronique Satre, Christophe Barbier, C Bosson, and Françoise Devillard
Subjects: MAPK/ERK pathway, Adult, Candidate gene, Prenatal diagnosis, RASopathy, Biology, Bioinformatics, Germline mutation, Fetus, Costello syndrome, Macroglossia, Pregnancy, Genetics, medicine, Humans, Genetics (clinical), Chromosomes, Human, Pair 13, Macrocephaly, Intracellular Signaling Peptides and Proteins, Membrane Proteins, General Medicine, Syndrome, medicine.disease, Megalencephaly, Female, medicine.symptom, Gene Deletion
Abstract: We report on a female fetus with macrocephaly and macroglossia harbouring 13q31.1 microdeletion encompassing three genes: SPRY2, NDFIP2 and RBM26. NDFIP2 protein is involved in ubiquitination and in Ras/mitogen-activated protein kinase (MAPK) signaling pathways. SPRY2 protein is part of Sprout protein family and inhibits the Ras/MAPK pathways. Ras/MAPK pathway plays important role in complex cellular programs including cell differentiation and proliferation. Germline mutations in genes encoding protein involved in the MAPK cascade is responsible for a wide family of developmental disorders known as RASopathies. Some RASopathies, such as Costello syndrome, present a phenotype with (relative) macrocephaly as perinatal features. However, prenatal-onset macroglossia are generally absent in this syndrome but rather suggestive of the Beckwith-Wiedemann syndrome for which molecular testing were negative. Phenotype-genotype correlation with patients from DECIPHER defines NDFIP2 and SPRY2 as a possible candidate genes for a RASopathy potentially responsible for the clinical features in the fetus. Finally, this original case of 13q31.1 microdeletion underlines the importance of array-CGH in prenatal diagnosis with sonographic signs such as macroglossia and/or macrocephaly. In this case, genetic investigation should be not limited to the search of well-known genetic causes and other genomic microdeletions should be considered as alternative diagnoses for macroglossia.
Published: 2015

61. Array-CGH in children with mild intellectual disability: a population-based study

Author: Marie David, Gaëlle Vieville, Françoise Devillard, Pierre-Simon Jouk, Véronique Satre, Florence Amblard, Klaus Dieterich, Christine Cans, and Charles Coutton
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Developmental Disabilities, Population, Protein Array Analysis, Intellectual Disability, Intellectual disability, medicine, Humans, Clinical significance, Copy-number variation, education, education.field_of_study, Comparative Genomic Hybridization, business.industry, Congenital malformations, medicine.disease, Population based study, Clinical trial, Pediatrics, Perinatology and Child Health, Etiology, Female, business
Abstract: Intellectual disability (ID) is characterized by limitation in intellectual function and adaptive behavior, with onset in childhood. Frequent identifiable causes of ID originate from chromosomal imbalances. During the last years, array-CGH has successfully contributed to improve the diagnostic detection rate of genetic abnormalities in patients with ID. Most array-CGH studies focused on patients with moderate or severe intellectual disability. Studies on genetic etiology in children with mild intellectual disability (ID) are very rare. We performed array-CGH analysis in 66 children with mild intellectual disability assessed in a population-based study and for whom no genetic etiology was identified. We found one or more copy number variations (CNVs) in 20 out of 66 (~30 %) patients with a mild ID. In eight of them (~12 %), the CNVs were certainly responsible for the phenotype and in six they were potentially pathogenic for ID. Altogether, array-CGH helped to determine the etiology of ID in 14 patients (~21 %). Conclusion: Our results underscore the clinical relevance of array-CGH to investigate the etiology of isolated idiopathic mild ID in patients or associated with even subtle dysmorphic features or congenital malformations.
Published: 2014

62. [Untitled]

Author: C Schulz, Klaus Dieterich, and Hendrik Lehnert
Subjects: endocrine system, medicine.medical_specialty, Central nucleus of the amygdala, Central nervous system, Solitary tract, General Medicine, Stimulus (physiology), Biochemistry, Cellular and Molecular Neuroscience, Corticotropin-releasing hormone, Autonomic nervous system, Endocrinology, Neurochemical, medicine.anatomical_structure, nervous system, Internal medicine, medicine, Locus coeruleus, Psychology, Neuroscience, hormones, hormone substitutes, and hormone antagonists
Abstract: Corticotropin-releasing factor (CRF) is both a major regulator of the hypothalamo-pituitary-adrenal (HPA) axis and the activity of the autonomic nervous system. Besides, it exerts numerous effects on other physiological functions such as appetite control, motor and cognitive behavior and immune function. The basis for these effects is constituted by its distribution in hypothalamic and extra-hypothalamic brain areas, the latter being represented by limbic structures such as the central nucleus of the amygdala or by brain stem neurons such as the locus coeruleus (LC) or nucleus of the solitary tract (NTS). The effects of CRF are mediated through recently described CRF-receptor subtypes, whose molecular biology, biochemistry and pharmacological regulation are discussed in detail. In the second part of this review, we will focus on the physiology of CRF-systems in the brain, with a particular emphasis on cardiovascular regulation, respiration, appetite control and stress-related behavior. Finally, the role of the locus coeruleus in the control of CRF-mediated behavioral activities is discussed. The interaction of noradrenergic and CRF-neurons clearly implies that CRF appears to directly activate LC neurons in a stressful situation, thus ultimately coordinating the bodily response to a stressful stimulus.
Published: 1998

63. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis

Author: André Mégarbané, Cécile Laroche, Isabelle Marty, Klaus Dieterich, Nicole Monnier, Damien Sternberg, Pierre-Simon Jouk, Jie Zhou, Susana Quijano-Roy, Daniela Avila Smirnow, Pascale Marcorelles, Robert Carlier, Sylvie Odent, Brigitte Estournet, Julien Fauré, Norma B. Romero, Sandra Mercier, Judith Melki, Joël Lunardi, INSERM U836, équipe 4, Muscles et pathologies, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Génétique et Procréation, CHU Grenoble-CHU Grenoble-Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant-Hôpital Couple Enfant, Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie Génétique et Moléculaire, CHU Grenoble-Institut de Biologie et de Pathologie (IBP)-CHU Grenoble-Institut de Biologie et de Pathologie (IBP), Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant, Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Anatomopathologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique et Procréation, CHU Grenoble, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Pyopathies, PHRC (AOM 10181), Inserm, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Roux-Buisson, Nathalie
Subjects: Central Nervous System, Pathology, Genetic Linkage, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Compound heterozygosity, Endothelins, Consanguinity, Mice, 0302 clinical medicine, MESH: Embryonic Development, MESH: Animals, 10. No inequality, Genetics (clinical), Arthrogryposis, Motor Neurons, 0303 health sciences, Mutation, Homozygote, Chromosome Mapping, Metalloendopeptidases, General Medicine, Anatomy, Muscle atrophy, 3. Good health, Pedigree, Phenotype, medicine.symptom, MESH: Motor Neurons, MESH: Homozygote, medicine.hormone, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, MESH: Arthrogryposis, MESH: Genetic Linkage, MESH: Metalloendopeptidases, Embryonic Development, Genes, Recessive, Biology, MESH: Phenotype, 03 medical and health sciences, Genetics, medicine, MESH: Central Nervous System, Animals, Humans, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Muscle contracture, MESH: Consanguinity, [SDV.GEN]Life Sciences [q-bio]/Genetics, Arthrogryposis multiplex congenita, MESH: Humans, Heterozygote advantage, MESH: Chromosome Mapping, 030217 neurology & neurosurgery
Abstract: International audience; Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes. Using a pangenomic approach, we demonstrated linkage of DA to chromosome 2q37 in two consanguineous families and the endothelin-converting enzyme like 1 (ECEL1) gene present in this region was associated with DA. Screening of a panel of 20 families with non-specific DA identified seven homozygous or compound heterozygous mutations of ECEL1 in a total of six families. Mutations resulted mostly in the absence of protein. ECEL1 is a neuronal endopeptidase predominantly expressed in the central nervous system and brain structures during fetal life in mice and human. ECEL1 plays a major role in intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis. A detailed review of clinical findings of DA patients with ECEL1 mutations revealed a homogeneous and recognizable phenotype characterized by limited knee flexion, flexed third to fifth fingers and severe muscle atrophy predominant on lower limbs and tongue that suggested a common pathogenic mechanism. We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction.
Published: 2012

64. Arthrogryposis multiplex congenita in an adult patient cohort: What are the limitations in activities in daily life?

Author: Marie Jaeger, Pierre-Simon Jouk, Dominic Pérennou, Shenhao Dai, Klaus Dieterich, Institut de rééducation, médecine et réadaptation neurologique, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique et procréation (Grenoble), Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Amyoplasia, Rehabilitation, Arthrogryposis multiplex congenita, Bathing, business.industry, medicine.medical_treatment, Walk, Activities in daily life, Functional independance mesure, medicine.disease, Functional Independence Measure, 3. Good health, medicine.anatomical_structure, Cohort, Toileting, Physical therapy, Medicine, Upper limb, Orthopedics and Sports Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; ObjectiveArthrogryposis multiplex congenita (AMC) is a clinical diagnosis characterized by the presence of at least two joint contractures at birth. Causes of AMC are numerous involving CNS, neuromuscular system, connective and bone tissue. This study is the first to describe disability patterns of a cohort of adults with AMC.Materials/patients and methodsThirty-nine patients (age 33.8 ± 11.5 years; 23 females) underwent between 2010 and 2016 a 4 day evaluation in the PMR ward during the multidisciplinary consultations for AMC at the Reference Centre of Congenital Anomalies in Grenoble: 25 with amyoplasia, 8 with distal arthrogryposis (DA), and 6 with other atypical diseases. All underwent the following functional assessments: functional independence measure (FIM) scale, functional ambulance classification (FAC) modified, six-minute walk test (SMWT), and a battery of functional tests for the upper limb (reaching, grasping, and pinches).ResultsMost patients suffering from AMC had modified independence, with an average FIM= 113.8 ± 12.3 (min = 71, max = 126, median = 117). Nearly all subjects had satisfactory Cognitive-FIM (34.9, min = 33, max = 35), while motor items of the FIM were altered (motor-FIM =78.4, min = 36, max = 91) especially bathing (5.9), upper body dressing (5.7), lower body dressing (5.3), toileting (5.4) and stairs (5.3). Regarding mobility limitation, the mean FAC score was 6.1/8. Only 34 patients could complete SMWT, with a limited mean distance: 338.6 ± 134 m (min = 100 m, max = 700 m). Walking was a major activity limitation for many patients, 28 patients needed to walk slowly on plain ground with surveillance or technical aids, 3 patients couldn’t walk. Regarding the upper limb, they could achieve 11.0 ± 5.5 of 16 tasks testing reaching movements (min = 1, max = 16), and 17.9 ± 6.8 of 22 tasks testing bilateral fine hand and finger movements (min = 0, max = 22). Activity limitations tended to be less severe in patients with DA.Discussion/ConclusionDespite obvious disabilities, most persons with AMC can live independently with few technical aids and compensations. Rehabilitation options were proposed accordingly, and patients’ satisfaction for this expert evaluation was high.
Published: 2016

65. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author: Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], 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), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, 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)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, 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), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413
Published: 2011

66. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population

Author: Mohamed Zahi, Marie-Christine Jacob, Sellama Nadifi, François Vialard, Yorgos Nikas, Raoudha Zouari, Abdelaziz Sefiani, Pierre-Simon Jouk, Hanane Bellayou, Nadia Prisant, Abdelali Zoghmar, Marie Roberte Guichaoua, Delphine Martinez, Klaus Dieterich, Joël Lunardi, Mehrdad Noruzinia, Mahmoud Kharouf, Sylviane Hennebicq, Stéphane Viville, Denise Escalier, Radu Harbuz, Isabelle Koscinski, Jacqueline Lornage, Pierre F. Ray, B. Sèle, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Laboratoire de Cytogénétique, CHI Poissy-Saint-Germain, Laboratoire de Génétique et Pathologie Moléculaire, Faculté de Médecine et Pharmacie Casablanca, Assistance médicale à la procréation, Biologie de reproduction - Stérilité [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Médecine de la Reproduction, Laboratoire de biologie de la reproduction, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de Biologie de la Reproduction, CHU Strasbourg, Department of Hematology, Tarbiat Modares University [Tehran], Département de génétique médicale, Institut National d'Hygiène, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre privé de Fécondation in vitro, RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant-Hôpital Couple-Enfant, Laboratoire d'Immunocytologie, EFS, Bases moléculaires et cellulaires des maladies génétiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Athens Innovative Microscopy, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARCHAMPS, Clinique de la reproduction les Jasmins, 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de génétique et procréation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Roux-Buisson, Nathalie
Subjects: Male, MESH: Tissue Donors, DNA Mutational Analysis, MESH: Africa, Northern, MESH: Flow Cytometry, Nucleic Acid Denaturation, medicine.disease_cause, Oogenesis, 0302 clinical medicine, Africa, Northern, Aurora Kinases, Aurora Kinase C, MESH: DNA Mutational Analysis, Chromatography, High Pressure Liquid, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, Mutation, 030219 obstetrics & reproductive medicine, MESH: Spermatozoa, Exons, General Medicine, Flow Cytometry, Spermatozoa, Tissue Donors, Meiosis, Meiotic cytokinesis, Female, MESH: Spermatogenesis, Infertility, MESH: Mutation, Population, Black People, MESH: Nucleic Acid Denaturation, Protein Serine-Threonine Kinases, Biology, Models, Biological, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spermatogenesis, education, MESH: Chromatography, High Pressure Liquid, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Models, Biological, MESH: Fertility, medicine.disease, MESH: Male, MESH: Meiosis, Fertility, MESH: African Continental Ancestry Group, MESH: Exons, MESH: Female
Abstract: International audience; Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.
Published: 2009

67. Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

Author: Joël Lunardi, Nicole Monnier, Paulette Mezin, Pierre-Simon Jouk, Isabelle Marty, Annick Labarre-Vila, Klaus Dieterich, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre de Reference des Maladies Neuromusculaires, Département de Génétique et Procréation, and Roux-Buisson, Nathalie
Subjects: Male, DNA Mutational Analysis, Inheritance Patterns, MESH: Tropomyosin, Tropomyosin, MESH: Genetic Markers, medicine.disease_cause, Myopathies, Nemaline, TPM2, MESH: Genotype, 0302 clinical medicine, Nemaline myopathy, MESH: Genetic Screening, MESH: Syndrome, MESH: DNA Mutational Analysis, Genetics (clinical), Genetics, 0303 health sciences, Mutation, MESH: Muscle, Skeletal, MESH: Genetic Predisposition to Disease, Syndrome, Null allele, MESH: Myopathies, Nemaline, Pedigree, RAPSN, medicine.anatomical_structure, Phenotype, Neurology, Child, Preschool, Female, Multiple pterygium syndrome, MESH: Algeria, Adult, Genetic Markers, MESH: Mutation, Genotype, MESH: Pedigree, Biology, MESH: Phenotype, Neuromuscular junction, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Predisposition to Disease, Genetic Testing, Muscle, Skeletal, 030304 developmental biology, MESH: Humans, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, Algeria, Pediatrics, Perinatology and Child Health, Neurology (clinical), MESH: Inheritance Patterns, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of beta-tropomyosin not compensated by expression of other beta-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.
Published: 2008

68. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility

Author: Pierre F. Ray, B. Sèle, Klaus Dieterich, Julia Perrin, Delphine Martinez, Pierre-Simon Jouk, Théophile Ohlmann, Baha Ben Amar, Sylviane Hennebicq, Sophie Rousseaux, Mohamed Zahi, Anne Karen Faure, Joël Lunardi, Ricardo Soto Rifo, Département de Génétique et Procréation, CHU Grenoble, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de FIV, Clinique Alboustane, Centre privé de Fécondation in vitro, Agence Nationale de la Recherche, Fondation d'Aide à la Recherche Organon, Direction de la Recherche Clinique du CHU de Grenoble., École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Roux-Buisson, Nathalie
Subjects: Male, Somatic cell, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Base Sequence, medicine.disease_cause, Male infertility, 0302 clinical medicine, Aurora Kinases, Aurora Kinase C, MESH: In Situ Hybridization, Fluorescence, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, Karyotype, Pedigree, 3. Good health, Infertility, MESH: Pedigree, Molecular Sequence Data, Protein Serine-Threonine Kinases, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Infertility, Male, Y chromosome, MESH: Protein-Serine-Threonine Kinases, Polyploidy, 03 medical and health sciences, MESH: Polyploidy, medicine, Humans, Point Mutation, Infertility, Male, 030304 developmental biology, MESH: Point Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, medicine.disease, MESH: Sperm Head, MESH: Male, Protein kinase domain, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sperm Head, MESH: Microsatellite Repeats, Microsatellite Repeats
Abstract: International audience; The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20-50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060). We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.
Published: 2007

69. Prévalence et caractéristiques étiologiques des enfants avec déficience intellectuelle légère dans le département de l’Isère

Author: J. Counillon, Pierre-Simon Jouk, A. Billette de Villemeur, M. David, Klaus Dieterich, F. Devillard, Christine Cans, Véronique Satre, Charles Coutton, G. Vieville, and F. Amblard
Subjects: Pediatrics, Perinatology and Child Health
Published: 2013

70. Methods and Tools for the Efficient Development of Automotive Electronics

Author: Klaus Dieterich
Subjects: Engineering, business.industry, business, Automotive electronics, Manufacturing engineering
Published: 1995

71. Optimized orbitals for the description of electron correlations

Author: Peter Fulde and Klaus Dieterich
Subjects: Linear combination of atomic orbitals, Chemistry, General Physics and Astronomy, Molecular orbital, Molecular orbital theory, Cubic harmonic, Astrophysics::Earth and Planetary Astrophysics, Complete active space, Physical and Theoretical Chemistry, Atomic physics, Slater-type orbital, Basis set, Natural bond orbital
Abstract: A method is described for the construction of (local) orbitals which are optimized for a correlation energy calculation. A distinction can be made between orbitals for intrabond and interbond correlations. The correlation energy is calculated with the optimized orbitals by applying the local ansatz. It is demonstrated for CH4 that the results agree with those of a CEPA. The number of optimized orbitals is considerably less than the number of pseudonatural orbitals (PNOs) which is required to attain the same accuracy. A physical interpretation of the orbitals is given and their transferability is briefly discussed.
Published: 1987

72. Le parcours diagnostique des enfants atteints d’Arthrogrypose Multiple Congénitale : description des pratiques actuelles à travers une cohorte monocentrique, et proposition de recommandations

Author: Le Tanno, Pauline, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), and Klaus Dieterich
Subjects: Arthrogryposis Multiplex Congenita, Paediatric cohort, Cohorte pédiatrique, Démarche diagnostique, Arthrogrypose Multiple Congénitale, Diagnostic assessment, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Introduction: Arthrogryposis multiplex congenita (AMC) defines congenital contractures involving two or more body areas. The prevalence is estimated between 1/3000 and 1/12000. More than 400 conditions may lead to AMC through foetal hypo/a-kinesia, making the aetiological diagnosis challenging. The objective of this work was to describe the aetiological management of children with AMC and to propose recommendations in order to optimize clinical practices. Material and methods: We conducted a retrospective single centre observational study. Patients had been evaluated at least once at a paediatric age in Grenoble University Hospital from 2007 to 2019. After determining the diagnostic status of these patients, data on their diagnostic procedure were gathered. A literature review was performed for each paraclinical investigation to discuss their relevance in the light of patients’ diagnoses, scientific knowledge, and benefit/risk or cost/benefit ratio. Results: 125 patients were included, 43% had Amyoplasia, 26% had distal arthrogryposis, and 31% had other forms. A definitive aetiological diagnosis was available for 63% of cases. We propose a two-time diagnostic process : first, non-invasive investigations that aim at classifying patients into one of the three groups, and then specific investigations targeting a subset of patients according to the expected yield and invasiveness. Conclusion: The diagnostic management of AMC patients has to result from a multidisciplinary approach. With the use of next generation sequencing, the aetiological assessment will be facilitated, but a relevant phenotyping will be paramount to guide their interpretation.; Introduction : L’Arthrogrypose Multiple Congénitale (AMC) correspond à des limitations articulaires touchant au moins deux niveaux. Sa prévalence est estimée entre 1/3000 et 1/12000. Le diagnostic étiologique est difficile car il en existe plus de 400 causes. L’objectif de ce travail est de décrire le parcours diagnostique des enfants atteints d’AMC et de proposer des recommandations afin d’optimiser les pratiques cliniques. Matériel et méthodes : Nous avons mené une étude rétrospective observationnelle monocentrique, incluant les enfants évalués au Centre Hospitalier Universitaire de Grenoble de 2007 à 2019. Nous avons collecté les informations sur leur parcours diagnostique, puis avons mené une revue de la littérature pour chaque investigation paraclinique afin d’en évaluer la pertinence à la lumière du diagnostic final des patients, des connaissances scientifiques, de leur bénéfices, risques et coûts. Résultats : Nous avons inclus un total de 125 patients, dont 43% cas d’Amyoplasie, 26% d’arthrogrypose distale et 31% d’autres formes. Un diagnostic étiologique était posé dans 63% des cas. Nous proposons une procédure diagnostique en deux temps: d’abord des investigations non invasives permettant d’orienter les patients vers l’un des trois groupes principaux, puis des investigations plus spécifiques avec des indications précises, en fonction de leur rendement attendu et de leur caractère invasif. Conclusion : L’approche diagnostique des enfants avec AMC doit résulter d’un travail pluridisciplinaire. L’utilisation croissante du séquençage de nouvelle génération facilitera cette démarche, mais le phénotypage restera essentiel pour guider leur interprétation.
Published: 2020

73. Mécanisme physiopathologique et spectre clinique liés aux mutations d’ECEL1, un gène majeur d’arthrogrypose

Author: Poreau, Brice, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Klaus Dieterich
Subjects: Score de sévérité, Test enzymatique, ECEL1, Arthrogrypose congénitale multiple, Endopeptidase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Dans la version électronique mise en ligne, une photographie a été masquée à la demande de l'auteur; Arthrogryposis multiplex congenita is a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. The prevalence is estimated between 1/3000 and 1/12000 births. Molecular investigations by Dieterich et al. at the university Hospital of Grenoble/France and at Grenoble Institute of Neurosciences INSERM U836 revealed mutations of ECEL1 (endothelin-converting enzyme like 1) associated with a new and recognizable phenotype of distal arthrogryposis (Dieterich et al., 2013). In this study, we tested the enzymatic activity of missense mutations. We performed experiments to test their expression and their cellular localization. We developed a new enzymatic peptidase assay for ECEL1. A decrease of the activity was found for one mutation p. C760R, located inside the catalytic domain (p
Published: 2014

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73 results on '"Klaus Dieterich"'

51. A framework to identify modifier genes in patients with Phelan-McDermid syndrome

52. 'Lowe syndrome: A particularly severe phenotype without clinical kidney involvement'

53. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

54. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

55. Delineation of the 3p14.1p13 microdeletion associated with syndromic distal limb contractures

56. Prevalence and characteristics of children with mild intellectual disability in a French county

57. Handicap in adults with arthrogryposis is severe, partly invisible and varies by genotype

58. Brachytelephalangic Chondrodysplasia Punctata: Prenatal Diagnosis and Postnatal Outcome

59. Rôle d’aurora kinase C (AURKC) dans la reproduction humaine

60. 13q31.1 microdeletion: A prenatal case report with macrocephaly and macroglossia

61. Array-CGH in children with mild intellectual disability: a population-based study

62. [Untitled]

63. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis

64. Arthrogryposis multiplex congenita in an adult patient cohort: What are the limitations in activities in daily life?

65. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

66. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population

67. Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

68. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility

69. Prévalence et caractéristiques étiologiques des enfants avec déficience intellectuelle légère dans le département de l’Isère

70. Methods and Tools for the Efficient Development of Automotive Electronics

71. Optimized orbitals for the description of electron correlations

72. Le parcours diagnostique des enfants atteints d’Arthrogrypose Multiple Congénitale : description des pratiques actuelles à travers une cohorte monocentrique, et proposition de recommandations

73. Mécanisme physiopathologique et spectre clinique liés aux mutations d’ECEL1, un gène majeur d’arthrogrypose

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73 results on '"Klaus Dieterich"'

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