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1. Subcutaneous anakinra in the management of refractory MIS-C in France

Author: Perrine Dusser, Alexandre Belot, Fanny Bajolle, Charlotte Kevorkian-Verguet, Ulrich Meinzer, Frédéric Huet, Soizic Tiriau, and Isabelle Kone-paut
Subjects: COVID-19, epidemiology, multisystem inflammatory syndrome in children, myocarditis, anakinra, interleukin-1, Pediatrics, RJ1-570
Abstract: IntroductionMultisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%–75%) and heart failure (52%–53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1 (IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition.MethodsThe prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra.ResultsOf the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%–45%). The average dose of anakinra received was 2.53 ± 1.3 mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48 h) improvement in myocardial function was observed (LVEF > 55%) with a concomitant significant decrease in myocardial enzymes (p
Published: 2024
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2. Changes in the clinical management of 5α-reductase type 2 and 17β-hydroxysteroid dehydrogenase type 3 deficiencies in France

Author: Estelle Bonnet, Mathias Winter, Delphine Mallet, Ingrid Plotton, Claire Bouvattier, Maryse Cartigny, Laetiti Martinerie, Michel Polak, Anne Bachelot, Frédéric Huet, Sabine Baron, Muriel Houang, Sylvie Soskin, Anne Lienhardt, Jérôme Bertherat, Cyril Amouroux, Aurore Bouty, Lise Duranteau, Rémi Besson, Alaa El Ghoneimi, Dinane Samara-Boustani, François Becmeur, Nicolas Kalfa, Françoise Paris, François Medjkane, Aude Brac de la Perrière, Patricia Bretones, Hervé Lejeune, Marc Nicolino, Pierre Mouriquand, Daniela-Brindusa Gorduza, and Claire-Lise Gay
Subjects: 5α-reductase type 2 deficiency, 17β-hydroxysteroid dehydrogenase type 3 deficiency, 46, xy disorders of sex development, sex assignment, change in practices, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.
Published: 2023
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3. The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders

Author: Julian Delanne, Ange-Line Bruel, Frédéric Huet, Sébastien Moutton, Sophie Nambot, Margot Grisval, Nada Houcinat, Paul Kuentz, Arthur Sorlin, Patrick Callier, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Daphné Lehalle, Salima El Chehadeh, Christine Francannet, Marine Lebrun, Laetitia Lambert, Marie-Line Jacquemont, Marion Gerard-Blanluet, Jean-Luc Alessandri, Marjolaine Willems, Julien Thevenon, Mondher Chouchane, Véronique Darmency, Clémence Fatus-Fauconnier, Sébastien Gay, Marie Bournez, Alice Masurel, Vanessa Leguy, Yannis Duffourd, Christophe Philippe, François Feillet, Laurence Faivre, and Christel Thauvin-Robinet
Subjects: Inherited metabolic disorders, Exome sequencing, Intellectual disability, Developmental delay, Genotype first, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable. Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
Published: 2021
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4. Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis

Author: Christophe Marguet, Véronique Houdouin, Isabelle Pin, Philippe Reix, Frédéric Huet, Marie Mittaine, Sophie Ramel, Nathalie Wizla-Derambure, Michel Abely, Marie-Laure Dalphin, Michael Fayon, Tiphaine Bihouée, Muriel Le Bourgeois, Eric Deneuville, Harriet Corvol, Muriel Laurans, Laure Couderc, Evelyne Leroux, and Ludovic Lémée
Subjects: Medicine
Abstract: Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.
Published: 2021
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5. CHANGES IN REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION–POSITIVE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 RATES IN ADULTS AND CHILDREN ACCORDING TO THE EPIDEMIC STAGES

Author: H. Haas, Nicoleta Ursulescu, Corinne Levy, Stéphane Béchet, François Vié le Sage, Philippe Bensaid, Cecile Bost bru, Cecile Fournial, Anne Sophie Romain, Muriel Lalande, Josette Raymond, Robert M. Cohen, Emmanuelle Dessioux, Véronique Hentgen, Jean Gashignard, Edeline Coinde, Alain Martinot, Charlotte Pons, Julie Toubiana, Romain Basmaci, Frédéric Huet, Comets, Emmanuelle, Groupe de Pathologie Infectieuse Pédiatrique [Paris] (GPIP), Société Française de Pédiatrie (SFP), Groupe d'Etude des Maladies Infectieuses Néonatales et Infantiles (GEMINI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-MRB-GRC, Centre de Recherche Clinique [Créteil] (CRC), Centre Hospitalier Intercommunal de Créteil (CHIC), Service de Pédiatrie-Urgences [Hopital Louis Mourier - APHP, Colombes], Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Victor Dupouy, Centre Hospitalier Général Néonatologie Ajaccio, Hôpitaux du Pays du Mont-Blanc, Centre hospitalier universitaire de Nantes (CHU Nantes), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Henri Duffaut (Avignon), Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), and Association Clinique et Thérapeutique Infantile du Val de Marne (ACTIV)
Subjects: Adult, Microbiology (medical), 2019-20 coronavirus outbreak, Pediatrics, medicine.medical_specialty, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, reverse transcription polymerase chain reaction, Betacoronavirus, 03 medical and health sciences, COVID-19 Testing, 0302 clinical medicine, children, 030225 pediatrics, adults, Humans, Medicine, 030212 general & internal medicine, Pediatrics, Perinatology, and Child Health, Child, Pandemics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Clinical Laboratory Techniques, Reverse Transcriptase Polymerase Chain Reaction, SARS-CoV-2, business.industry, Age Factors, COVID-19, biology.organism_classification, medicine.disease, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Confidence interval, 3. Good health, Reverse transcription polymerase chain reaction, Pneumonia, Real-time polymerase chain reaction, Infectious Diseases, Relative risk, Pediatrics, Perinatology and Child Health, France, Coronavirus Infections, business, severe acute respiratory syndrome coronavirus 2
Abstract: International audience; From March 2, 2020, to April 26, 2020, 52,588 reverse transcription polymerase chain reaction (RT-PCR) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were performed in France, 6490 in children and 46,098 in adults. The rate of RT-PCR-positive SARS-CoV-2 tests for children (5.9%) was always less than that for adults (20.3%) but vary according to the epidemic stage. The risk ratio of RT-PCR-positive SARS-CoV-2 tests for adults compared with children was 3.5 (95% confidence interval: 3.2-3.9) for the whole study period.
Published: 2020
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6. Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

Author: Christel Thauvin-Robinet, Véronique Darmency, Jean-Baptiste Rivière, Arthur Sorlin, Pierre Vabres, Marc Bardou, Frédéric Huet, Nawale Hadouiri, Alexis Arzimanoglou, Laurent Guibaud, Maxime Luu, Laurence Faivre, Virginie Carmignac, CCSD, Accord Elsevier, 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), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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, FHU TRANSLAD (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Dijon
Subjects: 0301 basic medicine, Oncology, Compassionate Use Trials, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Muscle hypertrophy, Craniofacial Abnormalities, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Everolimus, Child, Mechanistic target of rapamycin, Protein Kinase Inhibitors, Genetics (clinical), PI3K/AKT/mTOR pathway, Hypopigmentation, biology, business.industry, Mosaicism, TOR Serine-Threonine Kinases, Neuropsychology, General Medicine, Cortical dysplasia, medicine.disease, 3. Good health, Clinical trial, Malformations of Cortical Development, [SDV] Life Sciences [q-bio], 030104 developmental biology, Phenotype, Gain of Function Mutation, biology.protein, Female, Epilepsies, Partial, medicine.symptom, business, medicine.drug
Abstract: The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.
Published: 2020
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7. Pathology of Rotavirus-driven Multiple Organ Failure in a 16-month-old Boy

Author: Patrick Callier, Georges Tarris, Alexis de Rougemont, Frédéric Huet, Laurent Martin, Gaël Belliot, Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre National de Référence des virus entériques [CHU de Dijon] (CNR virus entériques), Service de Pathologie [CHU de Dijon], Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
Subjects: Microbiology (medical), Male, Rotavirus, Fatal outcome, Multiple Organ Failure, Autopsy, medicine.disease_cause, Rotavirus Infections, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, Antigen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030225 pediatrics, medicine, Humans, 030212 general & internal medicine, Human histo-blood group antigens, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Fetal Growth Retardation, Growth retardation, business.industry, Rotavirus severe acute gastroenteritis, Infant, virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Nephrons, Acute gastroenteritis, Acute Kidney Injury, Shock, Septic, 3. Good health, Gastroenteritis, Rotavirus infection, Infectious Diseases, Pediatrics, Perinatology and Child Health, Immunology, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.
Published: 2019
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8. Carriage of a Single Strain of Nontoxigenic Corynebacterium diphtheriae bv. Belfanti ( Corynebacterium belfantii ) in Four Patients with Cystic Fibrosis

Author: Frédéric Huet, K. Astruc, Marion Benouachkou, Catherine Neuwirth, Diane Pivot, Annlyse Fanton, Alexis Criscuolo, Serge Aho, Julie Toubiana, Edgar Badell-Ocando, Lucie Amoureux, Sylvain Brisse, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP), Centre national de Référence des Corynebactéries du Complexe Diphtheriae - National Reference Center Corynebacteria of the diphtheriae complex (CNR), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported financially by Dijon University Hospital, Institut Pasteur, and Public Health France., We acknowledge the help of Melody Dazas and Annick Carmi-Leroy for the microbiological characterization of the isolates. We thank the 'Plateforme de Microbiologie Mutualisée' from Institut Pasteur for genomic sequencing, Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), MESH: Cystic Fibrosis, Biovar, [SDV]Life Sciences [q-bio], Corynebacterium, MESH: Asymptomatic Infections, Cystic fibrosis, Microbiology, cystic fibrosis, 03 medical and health sciences, MESH: Corynebacterium diphtheriae, MESH: Anti-Bacterial Agents, medicine, Colonization, MESH: Diphtheria, 030304 developmental biology, Corynebacterium diphtheriae, 0303 health sciences, Corynebacterium diphtheriae bv. belfanti, MESH: Humans, biology, 030306 microbiology, business.industry, transmission, MESH: Adult, Antimicrobial, biology.organism_classification, medicine.disease, colonization, MESH: Male, 3. Good health, MESH: France, Carriage, genomic sequencing, epidemiology, business, MESH: Whole Genome Sequencing, MESH: Female
Abstract: International audience; Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae have not been reported so far. The aim of this article was to investigate the possibility of a cross-transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar Belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a period of 6 years and analyzed by microbiological methods and whole-genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole-genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient was found to have the same strain in two consecutive samplings performed 9 months apart. The strain was nontoxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. The idea of transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrated colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii), and the data suggest persistence and transmission of a unique strain during at least 6 years in a single CF patient care center.
Published: 2019
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9. Carriage of a single strain of non-toxigenic Corynebacterium diphtheriae biovar Belfanti (Corynebacterium belfantii) in four patients with cystic fibrosis

Author: Annlyse Fanton, Alexis Criscuolo, Catherine Neuwirth, Diane Pivot, Julie Toubiana, Serge Aho, Lucie Amoureux, Marion Benouachkou, Sylvain Brisse, Frédéric Huet, Edgar Badell-Ocando, and K. Astruc
Subjects: Whole genome sequencing, Corynebacterium diphtheriae, biology, business.industry, Biovar, Corynebacterium, biology.organism_classification, Antimicrobial, medicine.disease, Cystic fibrosis, Microbiology, Carriage, Medicine, Colonization, business
Abstract: Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae has not been reported so far. The aim of this article was to investigate the possibility of a cross transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a 6 years period and analyzed by microbiological methods and whole genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient had the same strain on two consecutive samplings nine months apart. The strain was non-toxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. Transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrates colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii) and shows persistence and transmission of a unique strain during at least six years in a single CF patient care center.Previous meeting presentationsThe information in this work was not previously presented in any meeting.Accession numbersThe genomic sequence data generated in this work were submitted to the European Nucleotide Archive and are available from the International Nucleotide Sequence Database Collaboration (NCBI/ENA/DDBJ) databases under project accession number PRJEB28372 and run data accession numbers ERR2757916 to ERR2757921.
Published: 2019
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10. Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Author: Ludmila Francescatto, Catherine Guettier-Bouttier, Jean-Baptiste Rivière, Evelyne Marinier, Olivier Goulet, Philippe Gauchez, Alexandre Fabre, Yves Rimet, Jean-Pierre Hugot, Aurélie Bourchany, Laurence Faivre, Catherine Badens, Arnauld Delarue, Emmanuel Gonzales, Frédéric Huet, Raphaelle Maudinas, Arnaud Blanchard, Nicholas Katsanis, Céline Brochier-Armanet, Christel Thauvin-Robinet, Sabine Sigaudy, Julien Thevenon, Caroline Lacoste, Karin Mazodier, Ange-Line Bruel, Emmanuelle Ecochard-Dugelay, Nicolas Lévy, Cécile de Leusse, Mina Komuta, Géraldine Hery, Yannis Duffourd, Jacques Sarles, Bertrand Roquelaure, Xavier Stéphenne, Patrice Bourgeois, Perciliz L. Tan, Clothilde Esteve, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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, Department of Pediatric Gastroenterology, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Assistance Publique-Hopitaux de Paris-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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 Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), 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), Signalisation calcique et interactions cellulaires dans le foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], 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)-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), Service de pédiatrie multidiciplinaire, 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), Service de Pédiatrie Multidisciplinaire, Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Origine, structure et évolution de la biodiversité (OSEB), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Center for Human Disease Modeling, Duke University [Durham], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille ( MMG ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité-Robert Debré Hospital-Assistance Publique-Hopitaux de Paris-Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Européen de Recherche en Imagerie médicale ( CERIMED ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Ecole Centrale de Marseille ( ECM ) -Institut Paoli-Calmettes-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Origine, structure et évolution de la biodiversité, Centre National de la Recherche Scientifique ( CNRS ), Duke university [Durham], UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance Publique-Hopitaux de Paris-Centre National de la Recherche Scientifique (CNRS), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Diarrhea, Male, Candidate gene, Adolescent, Bone fragility, Article, Bone and Bones, 03 medical and health sciences, Young Adult, Cholestasis, Loss of Function Mutation, GCUNC-45, Myosin, Genetics, Medicine, Animals, Humans, Family, Lymphocytes, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Hearing Loss, Gene, Genetics (clinical), Loss function, Zebrafish, business.industry, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Syndrome, Fibroblasts, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Concomitant, Child, Preschool, Immunology, Female, medicine.symptom, business, Gastrointestinal Motility
Abstract: International audience; Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
Published: 2018
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11. Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses

Author: Judith St-Onge, Anne-Laure Mosca-Boidron, Thibaud Jouan, Frédéric Tran-Mau-Them, Ange-Line Bruel, Laetitia Lambert, Sebastien Moutton, Aurélie Bourchany, Nolwenn Jean, Aurélia Jaquette, Christel Thauvin-Robinet, Daphné Lehalle, Elise Schaefer, Nada Houcinat, Charlotte Poe, Yannis Duffourd, Paul Kuentz, Salima El Chehadeh-Djebbar, Alice Masurel-Paulet, Martin Chevarin, Laurence Faivre, Sophie Nambot, Marjorie Willems, Mathilde Lefebvre, Nicole Laurent, Antonio Vitobello, Frédéric Huet, Julien Thevenon, Patrick Callier, Jean-Baptiste Rivière, Christophe Philippe, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD, Département de Génétique Clinique [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de Génétique Médicale, Hôpital Civil, Strasbourg, Centre de Génétique (Hôpital de la Pitié-Salpétrière, Paris), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de Pathologie [CHU de Dijon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Adult, Male, Exome sequencing, medicine.medical_specialty, Time Factors, Adolescent, Genetic counseling, Bioinformatics, Turnaround time, Sensitivity and Specificity, Undiagnosed genetic conditions, 03 medical and health sciences, Genetics, medicine, Humans, Exome, Genetic Testing, Medical diagnosis, Intensive care medicine, Child, Genetics (clinical), Genetic testing, Whole genome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, General Medicine, Sequence Analysis, DNA, Diagnostic turnaround time, 3. Good health, Clinical trial, 030104 developmental biology, Early Diagnosis, Child, Preschool, Female, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: IF 2.137; International audience; BACKGROUND AND OBJECTIVE:Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results.METHODS:WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation.RESULTS:The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials.CONCLUSIONS:This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Published: 2017
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12. Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A

Author: C. Thauvin-Robinet, Hery G, Nicholas Katsanis, Aurélie Fabre, Ecochard-Dugelay E, De Leusse C, Y. Rimet, Ange-Line Bruel, Delarue A, P. Gauchez, Xavier Stéphenne, Patrice Bourgeois, R. Maudinas, Ludmila Francescatto, Céline Brochier-Armanet, Yannis Duffourd, Arnaud Blanchard, Marinier E, Laurence Faivre, Olivier Goulet, Perciliz L. Tan, Caroline Lacoste, J. Sarles, Jean-Pierre Hugot, Clothilde Esteve, K. Mazodier, Sabine Sigaudy, Emmanuel Gonzales, Aurélie Bourchany, Nicolas Lévy, C. Guettier-Bouttier, Catherine Badens, Frédéric Huet, Jean-Baptiste Rivière, Julien Thevenon, Bertrand Roquelaure, and Mina Komuta
Subjects: Candidate gene, Cholestasis, In vivo, Concomitant, Myosin, Immunology, medicine, Cancer research, Biology, medicine.disease, Gene, Loss function, Exome sequencing
Abstract: Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
Published: 2017
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13. Randomised controlled trial demonstrates that fermented infant formula with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides reduces the incidence of infantile colic

Author: Derek Forde, Frédéric Huet, Thomas Ludwig, Jonathan O'b Hourihane, Philippe Alliet, Hetty Bouritius, Yvan Vandenplas, Stefaan Peeters, Growth and Development, Clinical sciences, Units of Pediatric Gastroenterology, Universitair Ziekenhuis Brussel, Nutricia Research, Kinderartsenpraktijk, Slaney Medical Centre, Algemeen Stedelijk Ziekenhuis Aalst, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Paediatric & Child Hlth, University College Cork (UCC), Nutricia Research, the Netherlands, Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, University College Cork ( UCC ), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)
Subjects: Colic, Cultured Milk Products, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Breastfeeding, Oligosaccharides, Prebiotic, Gastrointestinal tolerance, Gastroenterology, law.invention, 0302 clinical medicine, birth, Randomized controlled trial, law, Prospective Studies, functional gastrointestinal disorders, Prospective cohort study, Crying, Incidence (epidemiology), Regular Article, health, infant formula, General Medicine, Infantile colic, 3. Good health, mixture, prebiotic, Infant formula, 030211 gastroenterology & hepatology, medicine.symptom, Long chain, infantile colic, medicine.medical_specialty, life, 03 medical and health sciences, Double-Blind Method, children, 030225 pediatrics, Internal medicine, medicine, Humans, Pediatrics, Perinatology, and Child Health, childhood, business.industry, Infant, Newborn, Infant, constipation, medicine.disease, Surgery, Prebiotics, age, gastrointestinal tolerance, Pediatrics, Perinatology and Child Health, symptoms, Fermented formula, fermented formula, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Regular Articles
Abstract: Aim: We examined the effects on gastrointestinal (GI) tolerance of a novel infant formula that combined specific fermented formula (FERM) with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), with a 9: 1 ratio and concentration of 0.8 g/100 mL. Methods: This prospective, double-blind, randomised, controlled trial comprised 432 healthy, term infants aged 0-28 days whose parents decided to not start, or discontinued, breastfeeding. Infant formula with scGOS/lcFOS+50%FERM, scGOS/lcFOS+15%FERM, 50%FERM and scGOS/lcFOS were tested. Parents completed standardised seven-day diaries on GI symptoms, crying, sleeping and stool characteristics each month until the infants were 17 weeks. Results: All the formulas were well tolerated. At four weeks, the overall incidence of infantile colic was significantly lower (8%) with scGOS/lcFOS+50%FERM than scGOS/lcFOS (20%, p = 0.034) or 50% FERM (20%, p = 0.036). Longitudinal modelling showed that scGOS/lcFOS+ 50%FERM-fed infants also displayed a persistently lower daily crying duration and showed a consistent stool-softening effect than infants who received formula without scGOS/lcFOS. Conclusion: The combination of fermented formula with scGOS/lcFOS was well tolerated and showed a lower overall crying time, a lower incidence of infantile colic and a stool-softening effect in healthy term infants. These findings suggest for the first time that a specific infant formula has a preventive effect on infantile colic in formula-fed infants. Nutricia Research, the Netherlands, provided the funding to conduct the study. The funder contributed to the design of the study, interpretation of the findings and writing of the manuscript.
Published: 2017
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14. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Author: Patrick Callier, Angélique Quartier, Matthieu Jung, Brigitte Gilbert-Dussardier, Vincent des Portes, Claire Feger, Bernard Jost, Bénédicte Gérard, Stéphanie Le Gras, Daphné Lehalle, Elsa Nourisson, Anne-Sophie Casteleyn, Claire Redin, Julien Thevenon, Anne-Laure Mosca-Boidron, Laurence Faivre, Hélène Poquet, Frédéric Huet, Paul Kuentz, Christel Thauvin-Robinet, Véronique Geoffroy, Jean-Louis Mandel, Massimiliano Rossi, Gaetan Lesca, Alice Masurel, Patrick Edery, Benoit Trojak, Salima El Chehadeh, Stéphanie Maury, Jean Muller, Amélie Piton, 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, 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), Laboratoire de cytogénétique (CHU de Dijon), Service de psychiatrie générale et addictologie [CHU de Dijon], French Ministry of Health Fondation Jerome Lejeune Agence de la Biomedecine, CREGEMES Agence Nationale de la Recherche MENESR et Fondation Recherche Medicale Regional Council of Burgundy, ANR-10-IDEX-0002,UNISTRA,UNISTRA(2010), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), and ANR-10-IDEX-0002-02/10-IDEX-0002,UNISTRA,UNISTRA ( 2010 )
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, diagnosis, RNA Splicing, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Fragile X Mental Retardation Protein, 03 medical and health sciences, Exon, Genetic linkage, placebo-controlled trial, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Molecular genetics, Genetics, medicine, Humans, gene, Genetics (clinical), Mutation, intron 10, Siblings, Middle Aged, medicine.disease, FMR1, Human genetics, 3. Good health, Fragile X syndrome, developmental delay, of-the-literature, 030104 developmental biology, intellectual disability, Fragile X Syndrome, mental-retardation, Medical genetics, Female, point mutation, double-blind, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G > A (family 2) and a maternally inherited c.420-8A > G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
Published: 2017
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15. Changing facial phenotype in Cohen syndrome

Author: Bernard Aral, Nadège Gigot, François-Guillaume Debray, Alice Masurel-Paulet, Patrick Rump, Christel Thauvin-Robinet, Frédéric Huet, Muriel Holder-Espinasse, Marlène Rio, Laurence Duplomb, Patrick Callier, Edward Blair, Anne-Marie Frances, Salima El Chehadeh-Djebbar, Anne Moncla, and Laurence Faivre
Subjects: Male, Microcephaly, Developmental Disabilities, FEATURES, facial phenotype, Vesicular Transport Proteins, Myopia, CRITERIA, HETEROGENEITY, Child, Genetics (clinical), Genetics, Cohen syndrome, Retinal Degeneration, Hypotonia, VPS13B, Phenotype, medicine.anatomical_structure, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, medicine.medical_specialty, changing phenotype, Genetic counseling, Biology, Article, Fingers, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Obesity, Short philtrum, Auricle, NATURAL-HISTORY, medicine.disease, Dermatology, MUTATIONAL SPECTRUM, GENE, DELETIONS, stomatognathic diseases, Early Diagnosis, Face, Mutation, Square face, VPS13B gene
Abstract: Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.
Published: 2013
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16. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome

Author: Delphine Minot, Sophie Chancenotte, Paul Kuentz, Yvan Henrenger, Mélanie Archimbaud-Devilliers, Christel Thauvin-Robinet, Audrey Creppy, Aurore Curie, Ezzat Ghosn, Alice Masurel-Paulet, Marie Ruffier-Bourdet, Daphné Lehalle, Julien Thevenon, Nicole Philip, Marlène Bonnet, Frédéric Huet, Claire Redin, Laurence Faivre, Jean-Louis Mandel, Amélie Piton, Gaëlle Blanchard, Odile Perret, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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, Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Référent des Troubles du Langage et des Apprentissages [CHU Dijon] (CRTLA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), FHU TRANSLAD (CHU de Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), 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), 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, Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de Neuropédiatrie, Hospices Civils de Lyon (HCL), Université de Technologie de Compiègne (UTC), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Génétique Humaine, Collège de France (CdF (institution)), Regional Council of Burgundy Fondation Jerome Lejeune Agence de Biomedecine, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Reference Troubles Langages & Apprentissages, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), 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 ), FHU TRANSLAD, Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition ( L2C2 ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ), Université de Technologie de Compiègne [Compiègne] ( UTC ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génétique Humaine
Subjects: Male, 0301 basic medicine, Proband, Microcephaly, DNA Mutational Analysis, x-chromosome inactivation, SLC9A6, Gene mutation, exchanger, Epilepsy, Ocular Motility Disorders, 0302 clinical medicine, angelman-syndrome, X Chromosome Inactivation, Intellectual disability, microcephaly, Child, 10. No inequality, Genetics (clinical), Sequence Deletion, Genetics, Brain, Genetic Diseases, X-Linked, tool, Magnetic Resonance Imaging, Pedigree, 3. Good health, Phenotype, Female, Cerebellar atrophy, Christianson syndrome, medicine.symptom, Adult, Heterozygote, Sodium-Hydrogen Exchangers, Ataxia, Adolescent, learning disabilities linked mental-retardation, 03 medical and health sciences, cerebellar atrophy, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Angelman syndrome, medicine, Humans, Family, gene, Genetic Association Studies, business.industry, Facies, medicine.disease, 030104 developmental biology, splicing signals, Mutation, epilepsy, RNA Splice Sites, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.
Published: 2016
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17. Clinical severity and molecular characteristics of circulating and emerging rotaviruses in young children attending hospital emergency departments in France

Author: Jérôme Kaplon, Florence Morfin-Sherpa, D. Gendrel, Christopher Payan, A. Schnuriger, Anne Decoster, Sylvie Pillet, J.-F. Meritet, Aurélie Guigon, François Dubos, Bruno Pozzetto, M.-C. Legrand-Guillien, Céline Fremy, C. Bouquignaud, Y. Gillet, M. Rodiere, Didier Hober, Y. Mekki, Ronald Colimon, Pierre Lebon, O. Mory, A. Beby-Defaux, Sophie Alain, Stéphane Bonacorsi, Bruno Lina, Gisèle Lagathu, J.-L. Stephan, M. Chouchane, Pierre Pothier, A. Garbarg-Chenon, L. Mendes-Martins, R. Maudinas, Jérôme Guinard, Frédéric Huet, Patricia Mariani, J. Languepin, A. Minoui-Tran, A. de Rougemont, Mouna Lazrek, Véronique Avettand-Fenoel, Vincent Foulongne, Gérard Agius, Astrid Vabret, Denis Oriot, Serge Aho, Mathie Lorrot, UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), Centre National de Référence des virus entériques [CHU de Dijon] (CNR virus entériques), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de sérologie-virologie (CHU de Dijon), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire Interactions Muqueuses Agents Transmissibles (LIMA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Virologie Humaine et Moléculaire [Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier de Charleville-Mezières, Service de pédiatrie (CHU de Dijon), Hôpital du Bocage, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Cadi Ayyad [Marrakech] (UCA), Groupe Hospitalier de l'institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), Teaching hospital, CHU Limoges, Service d'urgence et de réanimation pédiatriques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Virologie et pathogenèse virale (VPV), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), ONERA - The French Aerospace Lab [Palaiseau], ONERA-Université Paris Saclay (COmUE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Virologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), University Hospital and University Jean Monnet, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Grenoble Alpes (UGA), Palmipèdes à Foie Gras (UEPFG), Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, ONERA, Station de recherches sur la vache laitière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Cochin [AP-HP], Institut Curie, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), CHU Orléans, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Male, Rotavirus, Pediatrics, Emerging rotavirus, medicine.disease_cause, Group A, Communicable Diseases, Emerging, Severity of Illness Index, Feces, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genotype, Prevalence, Clinical severity, Acute gastroenteritis, Phylogeny, ComputingMilieux_MISCELLANEOUS, Incidence (epidemiology), General Medicine, Diarrhoea, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, France, Seasons, Emergency Service, Hospital, Reassortant Viruses, Microbiology (medical), medicine.medical_specialty, Genotyping, 030106 microbiology, Rotavirus Infections, Severity, 03 medical and health sciences, medicine, Animals, Humans, business.industry, Infant, Newborn, Infant, Relative stability, 030104 developmental biology, business
Abstract: International audience; Group A rotavirus (RVA) is the leading cause of acute gastroenteritis in young children worldwide. A prospective surveillance network has been set up to investigate the virological and clinical features of RVA infections and to detect the emergence of potentially epidemic strains in France. From 2009 to 2014, RVA-positive stool samples were collected from 4800 children
Published: 2016
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18. Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Author: Julien Thevenon, Céline Souchay, Gail K Seabold, Inna Dygai-Cochet, Patrick Callier, Sébastien Gay, Lucie Corbin, Laurence Duplomb, Christel Thauvin-Robinet, Alice Masurel-Paulet, Salima El Chehadeh, Magali Avila, Delphine Minot, Eric Guedj, Sophie Chancenotte, Marlène Bonnet, Daphne Lehalle, Ya-Xian Wang, Paul Kuentz, Frédéric Huet, Anne-Laure Mosca-Boidron, Nathalie Marle, Ronald S Petralia, Laurence Faivre, 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 d'Etude de l'Apprentissage et du Développement [Dijon] (LEAD), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB), Neurochem lab (NIDCD), Nationale Institute of Health, Service de Médecine Nucléaire, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre Hospitalier Chalon-sur-Saône William Morey, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Référent des Troubles du Langage et des Apprentissages [CHU Dijon] (CRTLA ), Laboratoire de cytogénétique (CHU de Dijon), Regional council of Burgundy NIDCD/NIH, 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 d'Etude de l'Apprentissage et du Développement [Dijon] ( LEAD ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Neurochem lab ( NIDCD ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Reference Troubles Langages & Apprentissages, IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Hôpital de la Timone [CHU - APHM] (TIMONE), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Candidate gene, family, speech, Hippocampal formation, Rats, Sprague-Dawley, 0302 clinical medicine, Borderline intellectual functioning, Neuropsychological assessment, Child, disorders, Genetics (clinical), Cells, Cultured, adhesion-like molecules, Membrane Glycoproteins, medicine.diagnostic_test, Learning Disabilities, Brain, Magnetic Resonance Imaging, 3. Good health, Pedigree, Memory, Short-Term, Brain size, Female, Adult, Heterozygote, nmda receptor, autism, Nerve Tissue Proteins, Biology, Receptors, N-Methyl-D-Aspartate, Article, 03 medical and health sciences, Fluorodeoxyglucose F18, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, expression, Genetics, medicine, Animals, Humans, Memory Disorders, language, Genetic heterogeneity, Working memory, Membrane Proteins, down-syndrome, Rats, 030104 developmental biology, Endophenotype, Positron-Emission Tomography, Synapses, short-term, Radiopharmaceuticals, Neuroscience, 030217 neurology & neurosurgery, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.
Published: 2016
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19. 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

Author: Laurence Faivre, Marie-Ange Delrue, Nathalie Marle, Fanny Morice-Picard, Pierre-Simon Jouk, Delphine Héron, Alice Goldenberg, Stéphanie Perez-Martin, Julien Thevenon, Frédéric Huet, Véronique Dulieu, Alice Masurel, Patricia Calenda, Patrick Callier, Salima El Chehadeh, Sylvie Manouvrier-Hanu, Sophie Dupuis-Girod, Pascale Saugier-Veber, Gipsy Billy-Lopez, Joris Andrieux, Paul Kuentz, Ghislaine Plessis, Christel Thauvin-Robinet, Géraldine Joly-Helas, Sophie Nambot, Mathilde Lefebvre, Charles Coutton, Anne-Laure Mosca-Boidron, Caroline Rooryck, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de Cardiologie, Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de cytogénétique (CHU de Dijon), Pôle Rééducation - Réadaptation (Médecine Physique et Réadaptation) (CHU de Dijon), Service de pédiatrie (CHU de Dijon), EDF ( EDF ), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre Hospitalier Universitaire [Grenoble] ( CHU ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de génétique médicale, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies Rares - Génétique et Métabolisme ( MRGM ), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux], Service de génétique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique, Hospices Civils de Lyon ( HCL ) -Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Groupe Hospitalier Est, Regional council of Burgundy, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU 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, EDF (EDF), Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), 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 Grenoble Alpes [2016-2019] (UGA [2016-2019])-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 Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies Rares - Génétique et Métabolisme (MRGM), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 0301 basic medicine, Male, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Haploinsufficiency, cerebral hypomyelination, west-syndrome, Bioinformatics, Craniofacial Abnormalities, 0302 clinical medicine, Intellectual disability, STXBP1, Child, Genetics (clinical), Nail patella syndrome, Genetics, Endoglin, Syndrome, 3. Good health, developmental delay, Phenotype, intellectual disability, Medical genetics, Female, Chromosome Deletion, Chromosomes, Human, Pair 9, medicine.medical_specialty, Adolescent, LIM-Homeodomain Proteins, Biology, Contiguous gene syndrome, Article, 03 medical and health sciences, Munc18 Proteins, Genetic linkage, medicine, Humans, de-novo mutations, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, disease, Epilepsy, infantile epileptic encephalopathy, association, deletions, medicine.disease, Human genetics, 030104 developmental biology, nail-patella syndrome, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneousmucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.
Published: 2016
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20. Partly Fermented Infant Formulae With Specific Oligosaccharides Support Adequate Infant Growth and Are Well-Tolerated

Author: Umberto Simeoni, Christoph Savagner, Gérard Beley, Yvan Vandenplas, Marieke Abrahamse-Berkeveld, Jonathan O'b Hourihane, Frédéric Huet, Sebastian Tims, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Laboratory of Microbiology, Wageningen University and Research [Wageningen] (WUR), Maison de l'enfant Essey, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Units of Pediatric Gastroenterology, Universitair Ziekenhuis Brussel, Dept Paediat & Child Hlth, University College Cork (UCC), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Wageningen University and Research Centre [Wageningen] ( WUR ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), University College Cork ( UCC ), Growth and Development, and Clinical sciences
Subjects: 0301 basic medicine, safety, Male, Clostridium difficile/isolation & purification, Double-Blind Method, Feces/microbiology, Female, Follow-Up Studies, Humans, Infant, Infant Formula/adverse effects, Infant, Newborn, Oligosaccharides/adverse effects, Outcome Assessment (Health Care), Prospective Studies, Weight Gain, Population, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Oligosaccharides, 030209 endocrinology & metabolism, Secretory Immunoglobulin A, 03 medical and health sciences, Feces, 0302 clinical medicine, Animal science, Primary outcome, Outcome Assessment, Health Care, Original Article: Nutrition, microbiota, Medicine, Food science, education, fermented formula, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, education.field_of_study, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030109 nutrition & dietetics, business.industry, Clostridioides difficile, Gastroenterology, Anthropometry, Infant Formula, 3. Good health, Pediatrics, Perinatology and Child Health, Normal growth, Fermentation, medicine.symptom, Gastrointestinal function, business, Weight gain, scGOS/lcFOS
Abstract: Objective: Fermented formulae (FERM) and a specific mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1) have a potential beneficial effect on gastrointestinal function and microbiota development in infants. The present study assessed the safety and tolerance of the combination of partly fermented infant milk formulae and scGOS/lcFOS compared with either 1 feature, in healthy term infants. Methods: Four hundred thirty-two infants were enrolled before 28 days of age and followed up to 17 weeks of age and assigned to 1 of the 4 groups: (i) formula with scGOS/lcFOS, (ii) scGOS/lcFOS + 15% FERM, (iii) scGOS/lcFOS + 50% FERM, or (iv) 50% fermented formula (50% FERM). Primary outcome was daily weight gain during intervention (equivalence criterion: difference in daily weight gain ≤3 g/day). Infants’ anthropometrics, formula intake, number, and type of (serious) AEs were monitored monthly. Stool samples were collected at baseline and after 17 weeks for analysis of physiological and microbiological parameters. Results: Equivalence of weight gain per day was demonstrated in both the intention-to-treat and per-protocol population, with a mean weight gain (SD) of 29.7 (6.1), 28.2 (4.8), 28.5 (5.0), and 28.7 (5.9) g/day for the groups i to iv respectively. No differences were observed in other growth parameters, formula intake, and the number or severity of AEs. In all scGOS/lcFOS-containing formulae, a beneficial effect of scGOS/lcFOS was observed, indicated by the lower pH, lower Clostridium difficile levels, and higher secretory immunoglobulin A levels. Conclusions: The partly fermented infant milk formulae containing the specific mixture scGOS/lcFOS were well-tolerated and resulted in normal growth in healthy infants.
Published: 2016
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21. Note-taking as a main feature in a social networking platform for small and medium sized enterprises

Author: Claude Moulin, Sabine Bruaux, Ala Atrash, Frédéric Huet, Nathalie Darène, Marie-Hélène Abel, Heuristique et Diagnostic des Systèmes Complexes [Compiègne] (Heudiasyc), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Connaissance Organisation et Systèmes TECHniques (COSTECH), Université de Technologie de Compiègne (UTC), France Business School (France Business School), France Business School, and région picardie
Subjects: Knowledge management, business.industry, Process (engineering), Computer science, Ontology, Knowledge organization, Collaboration organizational learning, Semantic modeling, [INFO.INFO-WB]Computer Science [cs]/Web, Special needs, Ontology (information science), Semantic data model, Data science, Enterprise modelling, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Human-Computer Interaction, Arts and Humanities (miscellaneous), Small and medium-sized enterprise, Tacit knowledge, [SHS.GESTION]Humanities and Social Sciences/Business administration, business, General Psychology, Note-taking, Enterprise modeling
Abstract: We justify the role of taking notes and annotations within SMEs.We present an original semantic model for taking notes and annotations.Note and annotation are modeled as information resources.We present a collaborative web platform which is based on the semantic model. Managing knowledge (especially tacit knowledge) in small and medium sized enterprises has always been a challenge. They have special characteristics that are related to their size, structure and their members' coordination and collaboration. Theses specifications affect the process of knowledge management in such enterprises. In addition, they suffer from the missing of codified and standardized supports. All these factors illustrate the urgent need to provide them with an appropriate knowledge management solution. In this paper, the special needs for knowledge management in this kind of enterprises is illustrated. The importance of an effective note-taking tool is justified. A semantic model that takes into account these needs is presented. In addition, we explain our choice of MEMORAe web platform as a tool for knowledge organization. We also clarify the functionalities which have been added to MEMORAe platform in order to be dedicated to these enterprises. Finally, the web platform is introduced.
Published: 2015
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22. Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling

Author: Stylianos E. Antonarakis, Christel Thauvin-Robinet, Marilyn D. Resh, Laurence Faivre, Sandy Lambert, Isabelle Stévant, Christèle Desdoits-Lethimonier, Hiroshi Kurosaka, Paul A. Trainor, Federico Santoni, Christelle Borel, Bernard Jégou, Armine Matevossian, Antoine Rolland, Serge Nef, Frédéric Huet, Pierre Calvel, Françoise Kühne, Jadwiga Jaruzelska, Béatrice Conne, Patrick Callier, Séverine Mazaud-Guittot, Periklis Makrythanasis, Pascal Bernard, Céline Zimmermann, Michel Guipponi, Anne Vannier, Dagmar Wilhelm, Francine Mugneret, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Department of Genetic Medicine and Development [Geneva], Université de Genève (UNIGE), Monash University [Clayton], 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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Environnement viral et chimique & reproduction, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Biologie Moléculaire, EHESP-ARENES (EHESP-ARENES), École des Hautes Études en Santé Publique [EHESP] (EHESP), Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Department of Genetic Medicine and Development, University of Geneva Medical School, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ) -Heart Failure Research Center (HFRC), Université de Genève ( UNIGE ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ) -Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Virus, Environnement et Reproduction, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes ( GERHM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Department of Genetic Medicine and Development, University of Geneva Medical School-University of Geneva Medical School, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Université de Genève = University of Geneva (UNIGE), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Cell Fate Determination, Mice, Testis, Morphogenesis, Missense mutation, ddc:576.5, Genetics (clinical), Mutation, Homozygote, Cell Differentiation, Hedgehog signaling pathway, Pedigree, Cell biology, Female, Signal transduction, Signal Transduction, Research Article, medicine.medical_specialty, lcsh:QH426-470, Lipoylation, Molecular Sequence Data, Mutation, Missense, Biology, Palmitoylation, HHAT, Internal medicine, Genetics, medicine, Animals, Humans, Hedgehog Proteins, Amino Acid Sequence, Molecular Biology, Hedgehog, Ecology, Evolution, Behavior and Systematics, Disorder of Sex Development, 46,XY, [ SDV ] Life Sciences [q-bio], Sequence Homology, Amino Acid, Biology and Life Sciences, Sex Determination, lcsh:Genetics, Endocrinology, 46, XY Disorders of Sex Development/*genetics, Acyltransferases/chemistry/*genetics/metabolism, Hedgehog Proteins/*metabolism, Lipoylation/*genetics, Signal Transduction/*genetics, Testis/embryology, Lipid modification, Acyltransferases, Developmental Biology
Abstract: The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development., Author Summary Disorders of gonadal development represent a clinically and genetically heterogeneous class of DSD caused by defects in gonadal development and/or a failure of testis/ovarian differentiation. Unfortunately, in many cases the genetic aetiology of DSD is unknown, indicating that our knowledge of the factors mediating sex determination is limited. Using exome sequencing on a case of autosomal recessive syndromic 46,XY DSD with testicular dysgenesis and chondrodysplasia, we found a homozygous missense mutation (G287V) within the coding sequence of the O-acetyl-transferase HHAT gene. The HHAT gene encodes an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long range signaling potency of hedgehog secreted proteins. We found that HHAT is widely expressed in human organs during fetal development, including testes and ovaries around the time of sex determination. In vitro assays show that G287V mutation impairs HHAT palmitoyl-transferase activity and mice lacking functional Hhat exhibit testicular dysgenesis as well as other skeletal, neuronal and growth defects that recapitulate most aspects of the syndromic 46,XY DSD patient. These data provide the first clinical evidence of the essential role played by lipid modification of Hedgehog proteins in human testicular organogenesis and embryonic development.
Published: 2014
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23. Diversity of the clinical presentation of the MMR gene biallelic mutations

Author: Pierre Vabres, Emilie Bouvignies, Gaëlle Bougeard, Mario Tosi, Stéphanie Baert-Desurmont, Julie Tinat, David Malka, Brigitte Bressac-de Paillerets, Frédéric Huet, Laurence Olivier-Faivre, Caroline Chapusot, Cosette Martin, G. Couillault, Stéphanie Vasseur, Thierry Frebourg, Florence Le Pessot, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Technologie de Compiègne (UTC), Service de pédiatrie (CHU de Dijon), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
Subjects: Male, Cancer Research, medicine.disease_cause, DNA Mismatch Repair, 0302 clinical medicine, MESH: Child, PMS2, Age of Onset, Child, Index case, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Adenosine Triphosphatases, Genetics, 0303 health sciences, Mutation, MESH: Colorectal Neoplasms, Hereditary Nonpolyposis, Phenotype, Lynch syndrome, Pedigree, 3. Good health, DNA-Binding Proteins, MESH: DNA Mismatch Repair, MESH: DNA Repair Enzymes, Oncology, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, MESH: Lymphoma, T-Cell, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Adolescent, MESH: Pedigree, MESH: Age of Onset, Adenocarcinoma, Biology, Lymphoma, T-Cell, Frameshift mutation, Young Adult, 03 medical and health sciences, MESH: Mismatch Repair Endonuclease PMS2, medicine, MESH: Adenosine Triphosphatases, Humans, 030304 developmental biology, MESH: Adolescent, MESH: Humans, Rectal Neoplasms, MESH: Adenocarcinoma, MESH: Rectal Neoplasms, MESH: Haplotypes, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Human genetics, digestive system diseases, MESH: Male, MSH6, DNA Repair Enzymes, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer research, MESH: Female, MESH: DNA-Binding Proteins, MESH: Microsatellite Instability
Abstract: International audience; Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.
Published: 2014
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24. How functional economy would be an environmental economy? Mode of endogenization of environmental issues in functional economy

Author: Thierry Gidel, Justine Bisiaux, Frédéric Huet, Dominique Millet, Connaissance Organisation et Systèmes TECHniques (COSTECH), Université de Technologie de Compiègne (UTC), Safe Composition of Autonomous applications with Large-SCALE Execution environment (SCALE), COMmunications, Réseaux, systèmes Embarqués et Distribués (Laboratoire I3S - COMRED), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire d'Ingénierie des Systèmes Mécaniques et des MAtériaux (LISMMA), Université Paris 8 Vincennes-Saint-Denis (UP8)-SUPMECA - Institut supérieur de mécanique de Paris (SUPMECA), Laboratoire Conception des Systèmes Mécaniques et Robotiques - EA 7398 (COSMER), Université de Toulon (UTLN), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-COMmunications, Réseaux, systèmes Embarqués et Distribués (Laboratoire I3S - COMRED), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Information economy, Political economy of climate change, 020209 energy, media_common.quotation_subject, Research methodology, Mode (statistics), 02 engineering and technology, Ambiguity, 010501 environmental sciences, Business model, 01 natural sciences, [SPI.MECA.GEME]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Mechanical engineering [physics.class-ph], ComputingMilieux_GENERAL, Economy, 0202 electrical engineering, electronic engineering, information engineering, Economics, Production (economics), Economic system, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, media_common
Abstract: How functional economy would be an environmental economy? And more particularly: What is the mode of endogenization of environmental issues in Functional Economy? This paper reveals the ambiguity of environmental issues integration in Functional Economy through discussion of three proposals: environment is consecutive to Functional Economy; environment is necessary to Functional Economy, and Functional Economy is not correlated to environment. Our research methodology uses business models to evaluate if Functional Economy leads to environmental performances improvements. Business models typology reveals different levels of Functional Economy implementation. Then a correlation between those levels of Functional Economy integration and environmental issues is discussed. High-level Functional Economy has indeed a positive impact on environmental performances (for example companies with an “activist approach”) and low-level Functional Economy (still targeted on the good production) does not lead to environmental improvements. This research also reveals that economical issues drive Functional Economy implementation rather than environmental ones.
Published: 2014

25. C5orf42 is the major gene responsible for OFD syndrome type VI

Author: Louise Devisme, Jun-ichi Takanashi, Hülya Kayserili, Frédéric Huet, Jelena Martinovic, Catherine Noël, Tania Attié-Bitach, Muriel Holder, Nadia El Khartoufi, Estelle Lopez, Cédric Le Caignec, Jean-Baptiste Rivière, Pascale Kleinfinger, Ferechté Razavi, Hélène Ansart-Franquet, Nadège Gigot, Brunella Franco, Magali Avila, Irahara Kaori, Didier Lacombe, Julien Thevenon, Martine Le Merrer, Bernard Aral, Stanislas Lyonnet, Christel Thauvin-Robinet, Véronique Darmency-Stamboul, Bruno Reversade, Yeliz Güven, Lydie Burglen, Laurence Faivre, Lena Ho, Mohammad Shboul, Other departments, Lopez, E, Thauvin Robinet, C, Reversade, B, Khartoufi, Ne, Devisme, L, Holder, M, Ansart Franquet, H, Avila, M, Lacombe, D, Kleinfinger, P, Kaori, I, Takanashi, Ji, Le Merrer, M, Martinovic, J, Noël, C, Shboul, M, Ho, L, Güven, Y, Razavi, F, Burglen, L, Gigot, N, Darmency Stamboul, V, Thevenon, J, Aral, B, Kayserili, H, Huet, F, Lyonnet, S, Le Caignec, C, Franco, Brunella, Rivière, Jb, Faivre, L, and Attié Bitach, T.
Subjects: Adult, Male, Adolescent, Developmental Disabilities, Hamartoma, Biology, Nervous System Malformations, Microphthalmia, Ciliopathies, Joubert syndrome, Retina, Young Adult, Cerebellar Diseases, Cerebellum, Genetics, medicine, Humans, Abnormalities, Multiple, Exome, Eye Abnormalities, Child, Genetics (clinical), Exome sequencing, Alleles, Polydactyly, Corpus Callosum Agenesis, Membrane Proteins, Sequence Analysis, DNA, Kidney Diseases, Cystic, Orofaciodigital Syndromes, medicine.disease, Ciliopathy, Phenotype, Mutation, Female, Hypothalamic Diseases
Abstract: Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the “Joubert syndrome related disorders”. Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.
Published: 2014

26. VEB-1 in Achromobacter xylosoxidans from Cystic Fibrosis Patient, France

Author: Eliane Siebor, Carine Freby, André Pechinot, Frédéric Huet, Agathe Ogier-Desserrey, Anne Houzel, Stéphanie Perez-Martin, Jean-Marie Duez, Catherine Neuwirth, UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne ( UB ), Laboratoire de Microbiologie Médicale et Moléculaire, Laboratoire de Bactériologie (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Humbert, Murielle, Université de Bourgogne (UB), Laboratoire de bactériologie (CHU Dijon), Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
Subjects: Male, MESH : Molecular Sequence Data, integron, MESH: beta-Lactamases, lcsh:Medicine, MESH: Base Sequence, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Integron, Cystic fibrosis, Integrons, cystic fibrosis, ComputingMilieux_MISCELLANEOUS, MESH: Microbial Sensitivity Tests, 0303 health sciences, education.field_of_study, biology, Escherichia coli Proteins, MESH : beta-Lactamases, Achromobacter denitrificans, dispatch, Achromobacter xylosoxidans, MESH: Integrons, 3. Good health, MESH : Achromobacter denitrificans, France, medicine.symptom, MESH : Integrons, MESH: Cystic Fibrosis, Adolescent, MESH : Male, Molecular Sequence Data, Population, Microbial Sensitivity Tests, beta-Lactamases, Microbiology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, MESH : Adolescent, MESH : Cystic Fibrosis, medicine, Humans, Base sequence, lcsh:RC109-216, education, 030304 developmental biology, MESH: Adolescent, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, 030306 microbiology, business.industry, MESH : Humans, lcsh:R, Extended-spectrum beta-lactamase VEB-1, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, MESH: Achromobacter denitrificans, biology.protein, Sputum, MESH : Base Sequence, MESH : Microbial Sensitivity Tests, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract: Multidrug-resistant Achromobacter xylosoxidans was recovered from the sputum of a patient with cystic fibrosis. The VEB-1 extended-spectrum β-lactamase was detected on a class 1 integron. This first report of a VEB-1–producing isolate in this population requires further investigation to determine its distribution.
Published: 2006

27. 20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

Author: Sophie Chancenotte, Jean Muller, Amélie Piton, Katell Peoc'h, Hélène Poquet, Stéphanie Le Gras, Jean-Marie Launay, Jean-Louis Mandel, Anne-Sophie Jaeger, Laurence Faivre, Bénédicte Gérard, Jean-Michel Pinoit, Yvan Herenger, Bernard Jost, Christel Thauvin-Robinet, Alice Masurel, Julien Thevenon, Frédéric Huet, Claire Redin, Marlène Bonnet, and Julia Lauer
Subjects: Male, Models, Molecular, Brunner syndrome, Nonsense mutation, Mutation, Missense, Article, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Monoamine Oxidase, Genetics (clinical), Family Health, biology, Base Sequence, Genetic heterogeneity, Point mutation, High-Throughput Nucleotide Sequencing, medicine.disease, Pedigree, Protein Structure, Tertiary, Autism spectrum disorder, Attention Deficit and Disruptive Behavior Disorders, Child Development Disorders, Pervasive, biology.protein, Autism, Female, Monoamine oxidase A
Abstract: Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene–environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.
Published: 2013

28. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders

Author: Christel, Thauvin-Robinet, Anne, Munck, Frédéric, Huet, Alix, de Becdelièvre, Clément, Jimenez, Guy, Lalau, Elodie, Gautier, Jacques, Rollet, Jean, Flori, Raphaëlle, Nové-Josserand, Jean-Claude, Soufir, Alain, Haloun, Dominique, Hubert, Elise, Houssin, Gil, Bellis, Gilles, Rault, Albert, David, Laurent, Janny, Raphaël, Chiron, Nathalie, Rives, Dominique, Hairion, Patrick, Collignon, Antoine, Valeri, Gilles, Karsenty, Annick, Rossi, Marie-Pierre, Audrézet, Claude, Férec, Julie, Leclerc, Marie des, Georges, Mireille, Claustres, Thierry, Bienvenu, Bénédicte, Gérard, Pierre, Boisseau, Faïza, Cabet-Bey, David, Cheillan, Delphine, Feldmann, Christine, Clavel, Eric, Bieth, Albert, Iron, Brigitte, Simon-Bouy, Vincent, Izard, Julie, Steffann, Stéphane, Viville, Catherine, Costa, Véronique, Drouineaud, Patricia, Fauque, Christine, Binquet, Claire, Bonithon-Kopp, Mike A, Morris, Laurence, Faivre, Michel, Goossens, Michel, Roussey, Emmanuelle, Girodon, L, Weiss, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de pédiatrie (CHU de Dijon), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), CIC Cochin Pasteur (CIC 1417), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut national d'études démographiques (INED), Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Centre de Perharidy-Cellule de Coordination du Réseau Mucoviscidose (CECOREM), MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHRU de Brest, service de chirurgie urologique et de la transplantation reinale (CHU - BREST - Urologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Chirurgie urologique et transplantation rénale [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de génétique médicale [CHU Nantes], Service d'Endocrinologie Moléculaire et Maladies rares, Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Reims Champagne-Ardenne (URCA), CHU Toulouse [Toulouse], Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier de Versailles André Mignot (CHV), Université Paris Descartes - Paris 5 (UPD5), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Gamétogenèse et Qualité du Gamète (GQG), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Droit et Santé-Université de Lille, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de biochimie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Centre Hospitalier de Versailles (CHV)
Subjects: Infertility, Male, medicine.medical_specialty, Heterozygote, Cystic Fibrosis, Offspring, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Gene mutation, Compound heterozygosity, Asymptomatic, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Vas Deferens, Male Urogenital Diseases, Mutation Rate, Internal medicine, Prenatal Diagnosis, Genotype, Genetics, medicine, Humans, Family history, Child, Sweat, Genetics (clinical), Infertility, Male, 030304 developmental biology, 0303 health sciences, business.industry, Infant, Newborn, Infant, medicine.disease, 3. Good health, Phenotype, 030228 respiratory system, Child, Preschool, Immunology, Mutation, Female, medicine.symptom, business
Abstract: International audience; BACKGROUND:The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.METHODS:Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.RESULTS:97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.CONCLUSIONS:Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD
Published: 2013
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29. Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome

Author: N. Méjean, Nadège Gigot, Lydie Burglen, Estelle Lopez, Valérie Cormier-Daire, Didier Lacombe, Christel Thauvin-Robinet, John Dean, Marie Gonzales, Diana Rodriguez, Brunella Franco, Bérénice Doray, Melissa Crenshaw, Isabelle Desguerres, Patrick Callier, Laurent Pasquier, Tania Attié-Bitach, Frédéric Huet, Bernard Aral, Matthew Pastore, Véronique Darmency-Stamboul, Laurence Faivre, Darmency Stamboul, V, Burglen, L, Lopez, E, Mejean, N, Dean, J, Franco, Brunella, Rodriguez, D, Lacombe, D, Desguerres, I, Cormier Daire, V, Doray, B, Pasquier, L, Gonzales, M, Pastore, M, Crenshaw, Ml, Huet, F, Gigot, N, Aral, B, Callier, P, Faivre, L, Attié Bitach, T, and Thauvin Robinet, C.
Subjects: Molar tooth sign, Neuroimaging, Joubert syndrome, Frameshift mutation, Hypothalamic hamartoma, Genetics, medicine, Clinical genetic, Humans, Child, Mesoaxial polydactyly, Genetics (clinical), Polydactyly, business.industry, Brain, Infant, Proteins, General Medicine, Anatomy, Orofaciodigital Syndromes, medicine.disease, Magnetic Resonance Imaging, stomatognathic diseases, Child, Preschool, Mutation, Female, business, Tomography, X-Ray Computed
Abstract: Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the "Joubert syndrome related disorders" (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.
Published: 2013

30. PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

Author: Frédéric Huet, Michèle Mathieu-Dramard, Martine Caron-Debarle, Jeanne Amiel, C. Fagour, Christel Thauvin-Robinet, Olivier Lascols, Jacqueline Capeau, Patrick Callier, Marie-Laure Nunes, Damien Picot, Jean-Baptiste Rivière, Bernard Le Luyer, Martine Laville, Judith St-Onge, Delphine Héron, Yves Reznik, Sylvie Odent, Laurence Faivre, Pierre Bitoun, Julien Thevenon, Martine Auclair, Virginie Carmignac, Jean-Michel Petit, Magali Avila, Martine Le Merrer, Laurence Duplomb, Corinne Vigouroux, Department of Experimental Cardiology, Heart Failure Research Center (HFRC)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), 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), Pathologie de l'Adipocyte et des Cellules Hepatiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Center of Excellence in Neuroscience, CHU de Montréal, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Service de génétique médicale, CHU Amiens-Picardie, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Diabétologie, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Joseph Fourier - Grenoble 1 (UJF), Immunovirologie et polymorphisme génétique, Université de Nantes (UN), Laboratoire de cytogénétique (CHU de Dijon), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Cancers et préventions, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Recherche Saint-Antoine (UMRS893), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), 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 ), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU Tenon [AP-HP], Regional Council of Burgundy, a French government [ANR-10-IAHU], National Heart, Lung, and Blood Institute [HL-102923, HL-102924, HL-102925, HL-102926, HL-103010], ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ) -Heart Failure Research Center (HFRC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université de Montréal-CHU de Montréal, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Joseph Fourier - Grenoble 1 ( UJF ), Université de Nantes ( UN ), Centre de Recherche en Nutrition Humaine Rhône-Alpes ( CRNH ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon ( HCL ) -CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Unité Fonctionnelle de Génétique Clinique [CHU 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy]
Subjects: Proband, EXPRESSION, medicine.medical_specialty, 030209 endocrinology & metabolism, Biology, medicine.disease_cause, MICE LACKING, Short stature, 03 medical and health sciences, HYPOGLYCEMIA, 0302 clinical medicine, Insulin resistance, PIK3R1, Internal medicine, Report, medicine, Genetics, KINASE, Genetics(clinical), Lipoatrophy, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, AKT2, [SDV.GEN]Life Sciences [q-bio]/Genetics, RECEPTOR, medicine.disease, 3-KINASE, 3. Good health, Insulin receptor, Endocrinology, AUTOPHOSPHORYLATION, SHORT syndrome, biology.protein, SKELETAL-MUSCLE, GROWTH, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85 alpha, p55 alpha, and p50 alpha regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.
Published: 2013
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31. In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

Author: Anne H. Child, Christophe Béroud, Catherine Boileau, Jaime Sanchez del Pozo, Julie De Backer, Cyril Goizet, Jeanne Amiel, Lesley C. Adès, Pierre Vabres, Anne De Paepe, Julien Thevenon, Laurence Duplomb, Katherine Holman, Christel Thauvin-Robinet, Clarisse Baumann, Frédéric Huet, Ghislaine Plessis, Gwenaëlle Collod-Béroud, Bert Callewaert, Eloisa Arbustini, Henri Plauchu, Bernard Aral, Peter N. Robinson, Sophie Julia, Jean Baptiste Rivière, Valérie Cormier-Daire, Gavin Arno, Nadège Gigot, Marjolijn Renard, Lucie Gueneau, Guillaume Jondeau, Patrick Callier, Jean Benoît Courcet, Maja Di Rocco, Laurence Faivre, Virginie Carmignac, Estelle Lopez, Maurizia Grasso, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of medical genetics, Royal Alexandra Children's Hospital, Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], FHU TRANSLAD (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, Service de pédiatrie (CHU de Dijon), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Marfan Research Group, Westmead Hospital [Sydney], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Center for Medical Genetics [Ghent], Ghent University Hospital, Cardiac & Vascular Sciences, St Georges, University of London, Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de Biologie Moléculaire, Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, IRCCS - Pavia, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Service de Génétique Médicale du CHU de Bordeaux, Hôpital Robert Debré Paris, Hôpital Robert Debré, Université de Technologie de Compiègne (UTC), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Head of the Department of Medical Genetics, Center for Medical Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), 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 ), FHU TRANSLAD, 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 génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), The Children's Hospital at Westmead, Service de Génétique, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hôtel Dieu, Service de génétique, CHU Caen-Hôpital Clémenceau, Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Université de Technologie de Compiègne [Compiègne] ( UTC ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Ghent University [Belgium] ( UGENT ), COLLOD-BEROUD, Gwenaëlle, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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)-Centre National de la Recherche Scientifique (CNRS), and Universiteit Gent = Ghent University (UGENT)
Subjects: Male, Models, Molecular, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Marfan Syndrome, Arachnodactyly, Exon, 0302 clinical medicine, Gene Order, Missense mutation, Genetics(clinical), Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Exome sequencing, Genes, Dominant, Genetics, 0303 health sciences, Mutation, Shprintzen–Goldberg syndrome, Exons, Phenotype, Pedigree, DNA-Binding Proteins, Child, Preschool, Female, medicine.symptom, Adult, Adolescent, Molecular Sequence Data, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Camptodactyly, Craniosynostoses, Young Adult, stomatognathic system, Report, Proto-Oncogene Proteins, medicine, Humans, Amino Acid Sequence, 030304 developmental biology, Facies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Molecular biology, Protein Structure, Tertiary, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sequence Alignment, human activities, 030217 neurology & neurosurgery
Abstract: International audience; Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.
Published: 2012
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32. Search for a gene responsible for Floating-Harbor syndrome on chromosome 12q15q21.1

Author: Frédéric Huet, Alice Goldenberg, Armand Bottani, Sandy Lambert, Estelle Lopez, Laurence Duplomb, Bérénice Doray, Valérie Cormier-Daire, Patrick Callier, Anne Moncla, Bernard Aral, Laurence Faivre, Lucie Gueneau, Christel Thauvin-Robinet, Sylvie Odent, Damien Sanlaville, Didier Lacombe, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Hôpitaux Universitaires de Genève (HUG), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Cytogénétique (HFME), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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 ), Hôpitaux Universitaires de Genève ( HUG ), Service de Biologie Moléculaire, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Service de Cytogénétique ( HFME ), Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), and De Villemeur, Hervé
Subjects: Adult, Heart Septal Defects, Ventricular, Male, Candidate gene, Floating Harbor syndrome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Haploinsufficiency, Biology, Bioinformatics, Short stature, Craniofacial Abnormalities, 03 medical and health sciences, 12q15q21.1 microdeletion, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Growth Disorders, 030304 developmental biology, Sequence Deletion, Phenocopy, 0303 health sciences, Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 12, Genetic heterogeneity, 030305 genetics & heredity, Chromosome, High-Throughput Nucleotide Sequencing, high-throughput sequencing, medicine.disease, 3. Good health, Phenotype, Floating–Harbor syndrome, Child, Preschool, Mutation (genetic algorithm), Female, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; Floating-Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15-q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array-CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high-throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15-q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.
Published: 2012
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33. Growth during puberty in cystic fibrosis: a retrospective evaluation of a French cohort

Author: Marie Bournez, Frédéric Huet, and Gil Bellis
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Population, Nutritional Status, FRANCE, Growth, Standard score, Cystic fibrosis, Body Mass Index, CHILD_DEVELOPMENT, Forced Expiratory Volume, CYSTIC_FIBROSIS, medicine, Humans, Respiratory function, Child, education, Retrospective Studies, education.field_of_study, business.industry, Final height, COHORTS, medicine.disease, Body Height, Cross-Sectional Studies, PUBERTY, Pediatrics, Perinatology and Child Health, Cohort, Female, Age of onset, business, Body mass index
Abstract: Objectives To assess the longitudinal growth pattern in a large French cohort of patients with cystic fibrosis (CF), to determine to what extent puberty contributed to final height and to explore a potential relationship between growth, nutritional status and respiratory function. Methods Retrospective data were drawn from the French CF registry from 1999 to 2004. Height, weight and forced expiratory volume in 1 s (FEV 1 ) were recorded annually. Growth and velocity curves were compared with reference curves. Results 729 children with CF were included. In girls, height was similar to the reference population until age 11. Age at onset of puberty was the same as in reference girls. The pubertal spurt was lower than reference values and contributed less to the final adult height. In boys, the mean height was close to the reference mean until age 14 and was thereafter lower. Age at growth acceleration was similar to that in reference boys, but with an impaired peak height velocity (PHV). The final height was lower than in the general population (z score −0.73). No correlations were found between body mass index (BMI) and PHV. In girls, there was a weak but significant positive relationship between PHV and FEV 1 (r=0.17, p=0.02) Conclusions In this cohort, children with CF had a normal age of onset of puberty and pubertal spurt, with a low PHV. Puberty contributed less to final adult height, and neither BMI nor FEV 1 had a significant effect on pubertal height gain.
Published: 2012

34. The power of high-resolution non-targeted array-CGH in identifying intragenic rearrangements responsible for Cohen syndrome

Author: Anne-Laure Mosca-Boidron, Laurence Faivre, Veronica Cusin, Nadège Gigot, Salima El Chehadeh-Djebbar, Clémence Ragon, Frédéric Huet, Anne Moncla, Muriel Payet, Cornel Popovici, Anthonie J. van Essen, Bernard Aral, Christel Thauvin-Robinet, Alice Masurel-Paulet, Lucie Gueneau, Patrick Rump, Francine Mugneret, Patrick Callier, Nathalie Marle, Chantal Missirian, Jean-Raymond Teyssier, Irina Balikova, and Anne-Marie Frances
Subjects: Male, Genetics, Mutation, Cohen syndrome, Non targeted, DIAGNOSTIC-CRITERIA, Vesicular Transport Proteins, Biology, medicine.disease_cause, Bioinformatics, Compound heterozygosity, medicine.disease, Genome, GENE, VPS13B, DELINEATION, DELETIONS, Phenotype, medicine, Humans, Female, Allele, Gene, Genetics (clinical)
Abstract: We read with interest the article by Rivera-Brugues et al 1 in a recent issue of this journal describing 3 patients out of 1523 patients with unexplained mental retardation. Analysis by whole genome array-CGH (comparative genomic hybridisation) showed an intragenic heterozygous deletion in the VPS13B gene, and the subsequent sequencing of the VPS13B gene revealed by one-point mutation in the second allele in all three patients. In a previous study, we screened the VPS13B gene in 34 patients (28 families) with a suspicion of Cohen syndrome and identified 14 different mutations in 8 families (12 patients).2 The mutations were found in a compound heterozygous state in five families and in a homozygous state in one consanguineous family. In two other families (patients P1-F1, P2-F2 and P3-F2), only one heterozygous mutation was found (25% of families). Since the previous publication, 20 additional patients were screened, leading to the identification of compound heterozygosity in one patient and only one mutational event in four patients from three different families. All the patients with one or two mutational events in VPS13B were considered as having Cohen syndrome according to both Chandler's and Kolehmainen's criteria.3 4 Since the 244K array-CGH Agilent comprises 102 probes within the VPS13B gene (figure 1), we sought to identify a large intragenic event in two groups: group 1 included the five families in which one mutational event …
Published: 2011
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35. Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis

Author: Emmanuelle Girodon, E. Deneuville, Anne Munck, Michel Renouil, Marcel Guillot, Frédéric Huet, Isabelle Fajac, Marie des Georges, Albert Iron, Christel Thauvin-Robinet, Michel Roussey, Isabelle Sermet-Gaudelus, Delphine Roussel, Rola Abou-Taam, Stéphanie Bui, Gérard Lenoir, Aleksander Edelman, Cystic Fibrosis Center - hôpital Necker, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Expression des gènes des phosphorylations oxydatives mitochondriales. Maintenance de l'ADN MT, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Robert Debré, CRCM, Université Paris7, Assistance Publique - Hôpitaux de Paris, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pediatrics, Composite score, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Cystic fibrosis, Gastroenterology, Membrane Potentials, 03 medical and health sciences, 0302 clinical medicine, Neonatal Screening, Chlorides, 030225 pediatrics, Internal medicine, Genotype, medicine, Humans, Trypsin, Genetic Testing, Sweat, Sweat test, Genetic testing, Newborn screening, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, medicine.disease, Prognosis, 3. Good health, Nasal Mucosa, 030228 respiratory system, Potential difference, Lung disease, Child, Preschool, business, Follow-Up Studies
Abstract: International audience; BACKGROUND:A challenging problem arising from cystic fibrosis (CF) newborn screening is the significant number of infants with hypertrypsinaemia (HIRT) with sweat chloride levels in the intermediate range and only one or no identified CF-causing mutations.OBJECTIVES:To investigate the diagnostic value for CF of assessing CF transmembrane conductance regulator (CFTR) protein function by measuring nasal potential difference in children with HIRT.METHODS:A specially designed protocol was used to assess nasal potential difference (NPD) in 23 young children with HIRT (3 months-4 years) with inconclusive neonatal screening. Results were analysed with a composite score including CFTR-dependent sodium and chloride secretion. Results were correlated with genotype after extensive genetic screening and with clinical phenotype at follow-up 3 years later.RESULTS:NPD was interpretable for 21 children with HIRT: 13 had NPD composite scores in the CF range. All 13 were finally found to carry two CFTR mutations. At follow-up, nine had developed a chronic pulmonary disease consistent with a CF diagnosis. The sweat test could be repeated in nine children, and six had sweat chloride values >or=60 mmol/l. Of the eight children with normal NPD scores, only two had two CFTR mutations, both wide-spectrum mutations. None had developed a CF-like lung disease at follow-up. The sweat test could be reassessed in five of these eight children and all had sweat chloride values
Published: 2010
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36. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations

Author: Frédéric Huet, Peter N. Robinson, Guillaume Jondeau, Karin Mayer, Claire Bonithon-Kopp, Bertrand Chevallier, Uta Francke, Elodie Gautier, Laurence Faivre, Anne H. Child, Anatoli Kiotsekoglou, Christophe Béroud, Mireille Claustres, Bart Loeys, Maurizia Grasso, Gwenaëlle Collod-Béroud, Mine Arslan-Kirchner, Christine Binquet, Alice Masurel-Paulet, Catherine Boileau, Eloisa Arbustini, Julie De Backer, Anne De Paepe, Lesley C. Adès, Bert Callewaert, Dorothy Halliday, P Comeglio, Paul Coucke, Chantal Stheneur, 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), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Howard Hughes Medical Institute (HHMI), Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by a grant from the French Ministry of Health (grant Programme Hospitalier de Recherche Clinique 2004), Groupement d’Intérêt Scientifique Maladies Rares 2004, Bourse de la Société Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005, and ANR-05-PCOD-014. Drs Callewaert and Loeys are a research fellow and a senior clinical investigator, respectively, of the Fund for Scientific ResearchFlanders. Drs Child and Comeglio thank the Marfan Trust and the Bluff Field Charitable Fund for support., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Service de biochimie, d'hormonologie et de génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, and Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 )
Subjects: Male, Proband, Marfan syndrome, Pediatrics, CI— confidence interval, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, MESH : Child, Preschool, PTC—premature termination codon, AAD—ascending aortic dilation, 0302 clinical medicine, MESH: Genetic Screening, MESH : Child, MESH: Child, Medicine, MESH : Female, Family history, Child, Ectopia lentis, Aortic dissection, education.field_of_study, Dural ectasia, Microfilament Proteins, MESH: Follow-Up Studies, Connective tissue disease, 3. Good health, MFS—Marfan syndrome, Child, Preschool, Female, MESH : Mutation, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Adolescent, MESH : Microfilament Proteins, Abbreviations, MESH : Male, Population, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH: Microfilament Proteins, MESH : Adolescent, Humans, Genetic Testing, FBN1, education, childhood, MESH : Genetic Screening, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, MESH : Follow-Up Studies, medicine.disease, EL— ectopia lentis, MESH: Male, Surgery, Mutation, Pediatrics, Perinatology and Child Health, international criteria, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients
Published: 2009
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37. PLM-based approach for collaborative design between OEM and suppliers: case study of aeronautic industry

Author: Benoît Eynard, Thierry Gidel, Eric Bonjour, Farouk Belkadi, Frédéric Huet, Nadège Troussier, Université de Technologie de Compiègne (UTC), Centre de Recherches et d'Etudes Interdisciplinaires sur le Développement Durable (CREIDD), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Connaissance Organisation et Systèmes TECHniques (COSTECH), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Gaetano Cascini, Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), and Cascini
Subjects: [SPI.OTHER]Engineering Sciences [physics]/Other, 0209 industrial biotechnology, Engineering, Relation (database), Process (engineering), ComputerApplications_COMPUTERSINOTHERSYSTEMS, 02 engineering and technology, Fixture, PLM, [SPI.AUTO]Engineering Sciences [physics]/Automatic, 020901 industrial engineering & automation, Unified Modeling Language, 0202 electrical engineering, electronic engineering, information engineering, Innovative Organisation, Collaborative design, computer.programming_language, Structure (mathematical logic), business.industry, Original equipment manufacturer, Manufacturing engineering, UML, Systems engineering, Design process, 020201 artificial intelligence & image processing, Suppliers Integration, business, computer
Abstract: International audience; To achieve different assembly operations on the aircraft structure, the aeronautic OEM needs to create and manage various fixture tools. To cope with these needs, the OEM begun to adopt the supplier integration into the tooling development process. This paper presents a conceptual PLM-based approach to support new business partnership of different suppliers. The new business partnership aims to improve the role of supplier in the different tasks of design, configuration and fabrication of the tooling. The use of the PLM concepts is proposed to enhance the collaboration between OEM and the equipment's suppliers. UML models are proposed to specify the structure of the PLM solution. These models describe the relation between the aircraft assembly project, and the tooling design process.
Published: 2008
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38. Multicenter prospective study of the burden of rotavirus acute gastroenteritis in Europe, 2004-2005: The REVEAL study

Author: Carlo Giaquinto, Melanie Maxwell, Pierre Van Damme, Frédéric Huet, Leif Gothefors, Marie Van der Wielen, and REVEAL Study Group
Subjects: Male, Rotavirus, Pediatrics, medicine.medical_specialty, viruses, Immunology, Primary health care, Reoviridae, Enzyme-Linked Immunosorbent Assay, medicine.disease_cause, Rotavirus disease, Rotavirus Infections, Feces, fluids and secretions, medicine, Immunology and Allergy, Humans, Prospective Studies, Prospective cohort study, Child, Preschool, biology, business.industry, Incidence (epidemiology), Incidence, Environmental and Occupational Health, Infant, Newborn, Age Factors, virus diseases, Infant, Acute gastroenteritis, biology.organism_classification, Newborn, Child, Preschool, Europe, Female, Gastroenteritis, Public Health, Environmental and Occupational Health, Infectious Diseases, Multicenter study, Public Health, business
Abstract: Rotavirus is recognized as a significant cause of pediatric gastroenteritis worldwide. Comprehensive data on the burden of rotavirus disease in Europe were lacking.A prospective, multicenter, observational study was conducted during the 2004-2005 season in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom, to estimate the incidence of acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) in children5 years of age who require medical care in primary care, emergency department, and hospital settings.A total of 2846 children with AGE were included in the study, and, of the 2712 children for whom ELISA results were available, 1102 (40.6%) were found to be rotavirus positive. The estimated annual incidence of RVGE was 2.07-4.97 cases/100 children5 years of age, and it was highest among children 6-23 months of age, with 56.7%-74.2% of all RVGE cases occurring in children in this age group. Overall, RVGE was estimated to account for 27.8%-52.0% of AGE cases, and it was responsible for up to two-thirds of hospitalizations and emergency department consultations, as well as one-third of primary care consultations for AGE.Rotavirus infections account for a significant proportion of AGE cases in children5 years of age in Europe, many of whom require frequent primary care consultations or care in emergency department and/or hospital settings. The results of the present study suggest that routine rotavirus vaccination for infants6 months of age could significantly reduce the substantial burden of this potentially serious childhood disease.
Published: 2007

39. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Author: Emmanuel Raffo, Mathilde Lefebvre, Agathe Roubertie, Mondher Chouchane, Yannis Duffourd, Nathalie Villeneuve, Sandra Wahlen, Arnaud Lafon, Gaetan Lesca, Anne de Saint Martin, Delphine Héron, Laurent Villard, Cyril Mignot, Mathieu Milh, Alice Masurel-Paulet, Sylvie Odent, Laurence Faivre, Salima El Chehadeh, Annick Toutain, Julien Thevenon, Christel Thauvin-Robinet, Frédéric Huet, Bertrand Isidor, Clara Jugé, Jean-Baptiste Rivière, Christophe Philippe, Judith St-Onge, Damien Sanlaville, Véronique Darmency-Stamboul, François Feillet, 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 ), Epilepsie et ischémie cérébrale, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de référence des maladies héréditaires du métabolisme ( MaMEA Nancy-Brabois ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de Médecine Infantile I [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité. ( DevAH ), Université de Lorraine ( UL ), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de Cytogénétique ( HFME ), Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de pédiatrie (CHU de Dijon), Université de Technologie de Compiègne [Compiègne] ( UTC ), Service d'odontologie, médecine bucco-dentaire, chirurgie orale, implantologie (CHU de Dijon), Pôle de pédiatrie [CHU de Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg ( CHU de Strasbourg ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de génétique médicale, Hôpital Sud, Service de Génétique [CHRU Nancy], Villard, Laurent, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité (DevAH), Université de Lorraine (UL), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Cytogénétique (HFME), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Technologie de Compiègne (UTC), Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Génétique Médicale et Génomique Fonctionnelle (GMGF), 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)-Centre National de la Recherche Scientifique (CNRS), hôpital Sud, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, [SDV]Life Sciences [q-bio], Genes, Recessive, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Compound heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Seizures, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Report, medicine, Genetics, Recessive, Humans, Ictal, Genetics(clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), Exome sequencing, 030304 developmental biology, Subclinical infection, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Brain Diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV ] Life Sciences [q-bio], Symporters, Genetic heterogeneity, Citrate transport, medicine.disease, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], Genes, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.
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40. Factors associated with mucoid transition of Pseudomonas aeruginosa in cystic fibrosis patients

Author: Delphine Croisier, Frédéric Huet, Pascal Chavanet, K. Astruc, Benoit Martha, Lionel Piroth, and A. Fanton
Subjects: Adult, Male, Microbiology (medical), medicine.medical_specialty, Adolescent, medicine.disease_cause, Lower risk, Gastroenterology, Cystic fibrosis, Haemophilus influenzae, Sputum culture, Microbiology, Pathogenesis, Young Adult, Risk Factors, Internal medicine, Streptococcus pneumoniae, Pneumonia, Bacterial, medicine, Humans, mucoid transition, Pseudomonas Infections, Child, Retrospective Studies, medicine.diagnostic_test, Pseudomonas aeruginosa, business.industry, Polysaccharides, Bacterial, Sputum, Infant, General Medicine, medicine.disease, respiratory tract diseases, Infectious Diseases, Child, Preschool, Female, France, medicine.symptom, business
Abstract: Although the mucoid form of Pseudomonas aeruginosa (Pa) is largely responsible for the progression of lung disease in cystic fibrosis (CF), the relationship between factors relating daily-care regimes to mucoidy acquisition are as yet poorly investigated. Fifty-two CF patients registered at the CF centre of Dijon, France, were retrospectively evaluated from the date of Pa colonization either to the first -positive sputum culture for mucoid Pa (n = 26) or to the last culture in which the Pa remained non-mucoid (n = 26). All clinical, pathological and therapeutic events were recorded. The association between the parameters collected and mucoid transition of Pa was assessed in a Cox model with time-dependant covariables. The mean follow-up was 4.7 ± 4.3 years. Three independent parameters were associated with the higher risk of mucoid transition of Pa: persistence of Pa in sputum (OR 7.89; p
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41. 345 Safe treatment of infantile hemangiomas with propranolol despite baseline bradycardia

Author: Frédéric Huet, Sylvie Falcon-Eicher, Caroline Bonnet, Stéphanie Perez-Martin, Pierre Vabres, and B. Bonniaud
Subjects: business.industry, Anesthesia, medicine, cardiovascular system, Baseline bradycardia, Propranolol, Cardiology and Cardiovascular Medicine, business, medicine.drug
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42. A French collaborative study indicative of a very low classical-CF penetrance of R117H; implications for genetic counselling

Author: Elodie Gautier, M.-P. Audrézet, B. Gerard, Laurence Faivre, Thierry Bienvenu, J. Lafitte, Anne Munck, J. Flori, Frédéric Huet, G. Bellon, Mireille Claustres, I. Sermet, M. desGeorges, Claude Férec, Gil Bellis, Christine Binquet, Michel Roussey, Michel Goossens, Guy Lalau, Gilles Rault, Christel Thauvin-Robinet, E. Girodon, Eric Bieth, and D. Hubert
Subjects: Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, business.industry, Genetic counseling, Pediatrics, Perinatology and Child Health, medicine, Pediatrics, Perinatology, and Child Health, medicine.disease, business, Cystic fibrosis, Penetrance
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43. Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016

Author: Simon Le Hello, Alexandra Mailles, Lisa-A King, François-Xavier Weill, Delphine Sergentet-Thevenot, Réseau français hospitalier de surveillance du Shu pédiatrique, Nathalie Jourdan-Da Silva, Malika Gouali, Estelle Loukiadis, Stéphane Bonacorsi, Patricia Mariani-Kurkdjian, Dieter Van Cauteren, Chantal Loirat, Marie-Pierre Donguy, Mathias Bruyand, Henriette de Valk, Sophie Lefèvre, Département des maladies infectieuses, Institut de Veille Sanitaire (INVS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Direction Générale de l'Alimentation (DGAL), Ministère de l'agriculture, de l'agroalimentaire et de la forêt, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Members of the Réseau français hospitalier de surveillance du SHU pédiatrique Djamal-Dine Djeddi: Paediatric and Adolescent Medicine Departement, Centre Hospitalier Universitaire d’Amiens, Amiens, France. Lise Allard: Paediatric Departement, Centre Hospitalier Universitaire d’Angers, Angers, France. Sylvie Roullaud: Paediatric Departement, Centre Hospitalier d’Angoulême, Angoulême, France. François Nobili: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Besançon, Besançon, France. Brigitte Llanas: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. Loïc de Parscau: Paediatric Departement, Centre Hospitalier Régional Universitaire Morvan, Brest, France. Anne-Laure Sellier-Leclerc: Paediatric Nephrology Departement, hôpital Femme-Mère-Enfant, Bron, France. Philippe Eckart: Paediatric Departement, Centre Hospitalier Universitaire de Caen, Caen, France. Lucie Bessenay: Paediatric Departement, Centre Hospitalier Universitaire Estaing, Clermont Ferrand, France. Frédéric Huet: Paediatric Departement, Hôpital d’Enfants, Dijon, France. Guylhene Bourdat-Michel: Paediatric Departement, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. Corinne Guitton: Paediatric Departement, AP-HP Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France. Robert Novo: Paediatric Nephrology Departement, Hôpital Jeanne de Flandre, Centre Hospitalier Universitaire de Lille, Lille, France. Vincent Guigonis: Paediatric Departement, Centre Hospitalier Universitaire Limoges, Limoges, France. Marcel Guillot: Peadiatric Departement, Centre Hospitalier Robert Bisson, Lisieux, France. Michel Tsimaratos: Paediatric Nephrology Departement, Hôpital de la Timone, Marseille, France. Marc Fila: Paediatric Departement, Centre Hospitalier Universitaire de Montpellier, Montpellier, France. Gwenaelle Roussey-Kessler: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Nantes, Nantes, France. Etienne Berard: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Nice, Archet 2, Nice, France. Tim Ulinski: Paediatric Nephrology Departement, Hôpital Armand Trousseau, APHP, Paris, France. Chantal Loirat: Paediatric Nephrology Departement, Hôpital Robert Debré, APHP, Paris, France. Pauline Krug: Nephrology Departement, Hôpital Necker Enfants Malades, APHP, Paris, France. Violaine Lefranc: Paediatric Emergencies Departement, Centre Hospitalier Universitaire La Miletrie, Poitiers, France. Catherine Didier-Wright: Paediatric Department, Centre Hospitalier de la Région Annecienne, Pringy, France. Christine Pietremont: Nephrology Department, American Mémorial Hospital, Reims, France. Amélie Ryckewaert: Paediatric Nephrology Departement, Centre Hospitalier Universitaire Rennes, Rennes, France. Françoise Broux: Paediatric Nephrology Departement, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France. Marie-Pierre Lavocat: Paediatric Departement, Hôpital Nord, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France. Joelle Terzic: Paediatric Departement, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France. Stéphane Decramer: Pediatric Nephrology Department, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. Hubert Nivet: Pediatric Nephrology Department, Centre Hospitalier Universitaire de Tours, Tours, France. Isabelle Vrillon: Paediatric Nephrology Departement, Hôpitaux de Brabois, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France., Institut Pasteur [Paris] (IP), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-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), Centre National de Référence des Escherichia coli, Shigella et Salmonella - Bactéries pathogènes entériques (CNR-ESS), Santé publique France, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Infectious Disease Department [Saint Maurice], Agence Nationale de la Santé Publique [Saint-Maurice] (ANSP), and Mzembaba, Sandy
Subjects: Male, food-borne infections, Epidemiology, Shiga Toxins, medicine.disease_cause, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Disease Outbreaks, Feces, 0302 clinical medicine, fluids and secretions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, haemolytic uraemic syndrome, Medicine, 030212 general & internal medicine, Child, Escherichia coli Infections, 0303 health sciences, Shiga-Toxigenic Escherichia coli, Transmission (medicine), Escherichia coli Proteins, Incidence, E coli, 3. Good health, Population Surveillance, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, surveillance, France, medicine.medical_specialty, Shiga toxin producing Escherichia coli, Microbiology, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, children, Virology, Humans, Serologic Tests, HUS, Sex Distribution, Escherichia coli, Shiga toxin-producing Escherichia coli, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030306 microbiology, business.industry, Public Health, Environmental and Occupational Health, Infant, Outbreak, bacterial infections and mycoses, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Hemolytic-Uremic Syndrome, bacteria, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Haemolytic-uraemic syndrome, business
Abstract: Introduction Haemolytic uraemic syndrome (HUS) related to Shiga toxin-producing Escherichia coli (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged Aim We present the results of this surveillance between 2007 and 2016. Methods A voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation. Results Over the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26). Conclusions No major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.
Published: 2019
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