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1. P904: CILTACABTAGENE AUTOLEUCEL VS TREATMENTS FROM REAL-WORLD CLINICAL PRACTICE FOR TRIPLE CLASS EXPOSED PATIENTS WITH MULTIPLE MYELOMA: ADJUSTED COMPARISONS BASED ON CARTITUDE-1 AND THE EMMY FRENCH COHORT

Author: O. Decaux, C. Hulin, A. Perrot, M. Macro, L. Frenzel, J. Diels, N. J. Perualila, F. Ghilotti, B. Haefliger, E. Goldsztajn, S. Vernet, J. Thevenon, M. Willaime, N. Texier, J. M. Schecter, D. Madduri, C. Jackson, S. Valluri, and P. Moreau
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2022
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2. Unexpected diagnosis of a SHH nonsense variant causing a variable phenotype ranging from familial coloboma and Intellectual disability to isolated microcephaly

Author: A.-L. Bruel, J. Thevenon, F. Huet, N. Jean-Marcais, S. Odent, C. Dubourg, D. Lehalle, F. Tran Mau-Them, C. Philippe, S. Moutton, N. Houcinat, S. Gay, L. Guibaud, Y. Duffourd, J.-B. Rivière, L. Faivre, and C. Thauvin-Robinet
Subjects: 0301 basic medicine, Genetics, Microcephaly, Coloboma, media_common.quotation_subject, Nonsense, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 030104 developmental biology, Intellectual disability, Variable phenotype, medicine, Genetics (clinical), Exome sequencing, media_common
Published: 2018
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3. 局灶性真皮发育不全女性中的嵌合现象

Author: L. Heinz, E. Bourrat, P. Vabres, J. Thevenon, A. Hotz, S. Hörer, J. Küsel, A.D. Zimmer, S. Alter, R. Happle, and J. Fischer
Subjects: Dermatology
Published: 2019
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4. Comment quantifier la coordination des soins ? L’exemple de l’hémato-oncologie en France

Author: J. Thevenon, G. Cartron, J. Chevalier, G. Mercier, T. Kanouni, C. Duflos, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Janssen Pharmaceuticals
Subjects: MESH: Services de santé, 030505 public health, [SHS.STAT]Humanities and Social Sciences/Methods and statistics, Epidemiology, Public Health, Environmental and Occupational Health, Oncologie, MESH: Hôpitaux, [SDV.CAN]Life Sciences [q-bio]/Cancer, Coordination des soins, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030212 general & internal medicine, 0305 other medical science, Chimiothérapie
Abstract: International audience; La coordination des soins est définie comme une organisation volontaire destinée à fournir les soins appropriés à chaque patient. Quantifier cette coordination permettrait d’améliorer les soins reçus, notamment par des modalités tarifaires tenant compte explicitement de cet aspect. Notre objectif était de mesurer l’intensité de la coordination des soins chez des patients atteints d’hémopathie maligne en France.Méthodes : une étude rétrospective monocentrique a été menée au CHU de Montpellier. Tous les patients adultes atteints d’une hémopathie maligne, participant au programme de coordination des chimiothérapies intraveineuses en 2013 – 2015 et suivis pendant au moins trois mois ont été inclus. Les données ont été extraites des dossiers médicaux électroniques. L’intensité de la coordination a été définie comme la somme du nombre de contacts et d’actions de coordination. Nous avons examiné les contacts directs et téléphoniques entre les infirmières de la coordination et les autres intervenants, y compris le patient, les infirmières, le médecin généraliste, le pharmacien et le laboratoire. Les actions de coordination comprenaient le suivi du traitement, le suivi des bilans sanguins et d’autres actions. La probabilité d’avoir une intense intensité de coordination élevée a été modélisée en utilisant une régression logistique.Résultats : au total, 267 patients âgés de 57 ans (ET : 19) en moyenne ont été inclus. Le suivi médian était de 8,4 mois. L’intensité moyenne de coordination était égale à 11,5 (ET : 4,1) par patient et par mois, dont 2,8 contacts (ET : 1,3) et 8,7 (ET : 3) actions. Après ajustement, la probabilité de coordination intense était significativement plus élevée chez les patients de sexe masculin, atteints de leucémie lymphoïde chronique, et habitant à plus de 30 minutes du centre hospitalier (p < 0,05 pour tous).Discussion/conclusion : dans cette étude monocentrique, l’intensité de la coordination des soins pour les patients sous chimiothérapie intraveineuse pour une hémopathie maligne était expliquée par des caractéristiques démographiques, cliniques mais aussi géographiques des patients. Ces données pourraient servir à définir de nouvelles modalités tarifaires.
Published: 2018
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5. PS1264 FRENCH IBRUTINIB OBSERVATIONAL STUDY (FIRE): REAL-WORLD STUDY OF IBRUTINIB TREATMENT FOR MANTLE CELL LYMPHOMA (MCL) IN FRANCE

Author: K. le Dû, Guillaume Cartron, C. Kavanagh, S. Beauclair, C. Albrecht, B. Anglaret, Delphine Senecal, J. Thevenon, B. Slama, H. Orfeuvre, S. Le Gouill, Olivier Fitoussi, Lysiane Molina, Lucie Oberic, Alain Delmer, and Frederic Peyrade
Subjects: Oncology, medicine.medical_specialty, chemistry.chemical_compound, chemistry, business.industry, Internal medicine, Ibrutinib, medicine, Observational study, Mantle cell lymphoma, Hematology, medicine.disease, business
Published: 2019
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6. Les modifications de pratique clinique liées à l’arrivée du séquençage haut débit dans le diagnostic génétique des maladies du développement

Author: L, Demougeot, F, Houdayer, A, Pélissier, F, Mohrez, J, Thevenon, Y, Duffourd, S, Nambot, E, Gautier, C, Binquet, M, Rossi, D, Sanlaville, S, Béjean, C, Peyron, C, Thauvin-Robinet, L, Faivre, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Laboratoire d'Economie et de Gestion (LEG), Université de Bourgogne (UB)-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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre 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), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire d'Economie et de Gestion ( LEG ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre 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 ), Génétique des Anomalies du Développement ( GAD ), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB )
Subjects: Male, High-throughput sequencing, Adolescent, Developmental Disabilities, Genetics, Medical, High-Throughput Nucleotide Sequencing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Health Care Surveys, Diagnosis, Genomic medicine, Developmental abnormalities, Genetics, Humans, Female, France, Practice Patterns, Physicians', Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics
Abstract: IF 0.372; International audience; IntroductionThe arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses.MethodsGeneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken.ResultsOf those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures.DiscussionThe survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort?ConclusionIt is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine.
Published: 2018
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7. Accès précoce et données de vie réelle, l’exemple de l’Autorisation temporaire d’utilisation de cohorte (ATUc) daratumumab

Author: K. Mari, S. Vernet, J. Thevenon, and J. Boursicot-Beuzelin
Subjects: Epidemiology, Public Health, Environmental and Occupational Health
Abstract: Objectifs L’Autorisation temporaire d’utilisation (ATU) est une procedure specifique francaise delivree par l’Agence nationale de securite du medicament et des produits de sante (ANSM) qui permet aux patients l’acces precoce a des traitements innovants, repondants a un besoin medical important, avant la mise sur le marche (AMM). L’ATU nominative (ATUn) est delivree a la demande et sous la responsabilite du medecin prescripteur, avec un formulaire papier adresse a l’ANSM. Demandee par le laboratoire, l’ATU de cohorte (ATUc) avec un protocole d’utilisation therapeutique (PUT) permet d’encadrer le suivi et l’administration du traitement et precise les donnees a collecter pendant la duree de l’ATUc. Cette collecte de donnees doit repondre a deux exigences qui peuvent paraitre incompatibles : d’une part la surveillance etroite demandee par l’ANSM et de l’autre donner l’acces a un traitement a des patients en impasse therapeutique. L’ATUc, accordee le 08/04/16 par l’ANSM a Janssen pour daratumumab 20 mg/mL, illustre parfaitement ce paradigme. Methode L’ensemble des criteres definis et des donnees collectees pour valider chaque demande par les prescripteurs ont ete recueillies, via une plateforme digitale accessible de maniere securisee par internet. Le choix de dematerialiser la demande a permis d’accelerer l’acces puisque la validation par les pharmaciens s’est faite en 4,2 h en moyenne et en seulement 1,7 h par Janssen. Les donnees ont pu etre controlees directement sur la plateforme pour optimiser la saisie et leur qualite de remplissage. Ces donnees ont ete analysees par le laboratoire Janssen et transmises a l’ANSM, avec un rapport de synthese decrivant les caracteristiques des patients traites, les modalites effectives d’utilisation, les donnees d’efficacite et de pharmacovigilance. Resultats L’ATUc daratumumab a commence le 09/05/16 et s’est achevee le 20/06/16. Elle a inclus 180 patients (dont 50,6 % de femmes). L’âge median des patients etait de 66,8 ans. L’anciennete mediane de la maladie etait de 5,8 ans. Les patients avaient recu en mediane cinq lignes de traitement avant daratumumab. La plupart des patients (68,9 %) avec un ECOG Conclusion La mise a disposition d’une plateforme digitale apporte un meilleur recueil des donnees et facilite le circuit d’approbation a la fois pour les medecins et pharmaciens mais egalement pour le laboratoire. Son utilisation des les ATUn est a envisager. L’ATU, en dehors des essais cliniques, est un dispositif essentiel pour les patients en impasse therapeutique puisqu’elle permet qu’ils aient acces rapidement a un traitement qui n’est pas encore sur le marche ; cependant, le fait qu’elle soit limitee a la premiere indication pose question et merite d’etre discutee pour des extensions d’indication.
Published: 2018
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8. Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Author: S, El Chehadeh, R, Touraine, F, Prieur, W, Reardon, T, Bienvenu, S, Chantot-Bastaraud, M, Doco-Fenzy, E, Landais, C, Philippe, N, Marle, P, Callier, A-L, Mosca-Boidron, F, Mugneret, N, Le Meur, A, Goldenberg, A-M, Guerrot, P, Chambon, V, Satre, C, Coutton, P-S, Jouk, F, Devillard, K, Dieterich, A, Afenjar, L, Burglen, M-L, Moutard, M-C, Addor, S, Lebon, D, Martinet, J-L, Alessandri, B, Doray, M, Miguet, D, Devys, P, Saugier-Veber, S, Drunat, B, Aral, V, Kremer, S, Rondeau, A-C, Tabet, J, Thevenon, C, Thauvin-Robinet, N, Perreton, V, Des Portes, and L, Faivre
Subjects: Adult, Male, Chromosomes, Human, X, Adolescent, Methyl-CpG-Binding Protein 2, Genetic Counseling, Pedigree, Phenotype, Gene Duplication, Intellectual Disability, Mental Retardation, X-Linked, Humans, Female, Child
Abstract: Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
Published: 2016

9. Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: A 7-year national survey

Author: M, Lefebvre, D, Sanlaville, N, Marle, C, Thauvin-Robinet, E, Gautier, S E, Chehadeh, A-L, Mosca-Boidron, J, Thevenon, P, Edery, M-P, Alex-Cordier, M, Till, S, Lyonnet, V, Cormier-Daire, J, Amiel, A, Philippe, S, Romana, V, Malan, A, Afenjar, S, Marlin, S, Chantot-Bastaraud, P, Bitoun, B, Heron, E, Piparas, F, Morice-Picard, S, Moutton, N, Chassaing, A, Vigouroux-Castera, J, Lespinasse, S, Manouvrier-Hanu, O, Boute-Benejean, C, Vincent-Delorme, F, Petit, N L, Meur, M, Marti-Dramard, A-M, Guerrot, A, Goldenberg, S, Redon, C, Ferrec, S, Odent, C L, Caignec, S, Mercier, B, Gilbert-Dussardier, A, Toutain, S, Arpin, S, Blesson, I, Mortemousque, E, Schaefer, D, Martin, N, Philip, S, Sigaudy, T, Busa, C, Missirian, F, Giuliano, H K, Benailly, P K V, Kien, B, Leheup, C, Benneteau, L, Lambert, R, Caumes, P, Kuentz, I, François, D, Heron, B, Keren, E, Cretin, P, Callier, S, Julia, L, Faivre, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique (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), Université de Bourgogne (UB), Service de Génétique, Hospices Civils de Lyon (HCL), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), INSERM EMI0210 (EMI0210), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Hôpital Jean Verdier [AP-HP], Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Le Mans (CH Le Mans), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), 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), Hôpital l'Archet, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Dijon, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical Investigation Centre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Pain & Palliative Care Department, Université de Franche-Comté (UFC), Logiques de l'Agir ( UR 2274) (LdA), The authors thanks the Regional Council of Burgundy for their support., Jonchère, Laurent, 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), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne ( UB ), Hospices Civils de Lyon ( HCL ), Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Institut National de la Santé et de la Recherche Médicale, 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 ), INSERM EMI0210 ( EMI0210 ), 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)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Service de neurologie pédiatriques, Service de neuropédiatrie [Trousseau]-Centre de Référence des Maladies Lysosomales, Hôpital Jean Verdier, Maladies Rares - Génétique et Métabolisme ( MRGM ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Toulouse, Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), 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 ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Hôpital Bretonneau-CHRU Tours, CHU Le MAns, Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), 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 ), 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 Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de neuropédiatrie [Trousseau], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Université de Franche-Comté ( UFC ), Logiques de l'Agir - UFC ( LdA ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, 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 ), Logiques de l'Agir ( EA 2274) ( LdA ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, 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 ), Logiques de l'Agir ( EA 2274) (LdA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Comparative Genomic Hybridization, Physician-Patient Relations, [SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Genetic Diseases, Inborn, Genes, Recessive, Genetic Counseling, Genetic Diseases, X-Linked, Disclosure, [SDV.GEN] Life Sciences [q-bio]/Genetics, Microarray Analysis, [SDV] Life Sciences [q-bio], incidental findings, aCGH, Surveys and Questionnaires, Humans, Female, ethical issues, pre-test information, France, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Genes, Dominant, Retrospective Studies
Abstract: International audience; Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
Published: 2016
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10. Étude des manifestations buccodentaires sur une série de patients acromégales (Acrodent)

Author: Laurent Devoize, M. Batisse-Lignier, S. Roumeau, Salwan Maqdasy, Igor Tauveron, Ac. Melka-Laurian, and J. Thevenon
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Objectif Les manifestations orales de l’acromegalie sont mal connues. La litterature scientifique sur ce sujet est pauvre, avec de nombreuses controverses. Notre objectif est de faire un etat des lieux clinique et radiologique le plus precis possible de l’etat bucco-dentaire de ces patients. Methodes Nous avons evalue prospectivement l’etat bucco-dentaire de patients acromegales, gueris ou non. Apres recueil des caracteristiques de leur maladie, les patients ont repondu au questionnaire GOHAI evaluant leur qualite de vie orale puis beneficie d’un examen clinique stomatologique et radiologique par le meme specialiste experimente. Resultats Vingt-huit patients ont ete inclus, âge moyen 57,9 ± 16,2 ans, nombres d’annees median depuis le diagnostic : 8,5 ans, 50 % des patients avaient une maladie non controlee sur le plan hormonal. Le score GOHAI moyen est de 49,3 ± 7,8 soit une faible satisfaction de leur qualite de vie orale. Nous retrouvons une gingivite importante chez 14 patients (50 %) et des saignements gingivaux sans noter pour autant de maladie parodontale significative, probablement car la frequence d’un biotype gingival epais protecteur (7/28 ; 25 %) augmente. 3 patients (11 %) avaient des images radio-opaques du maxillaire (cementomes, dysplasies cementaires peri-apicales) et 10 (36 %) des exostoses (tori) maxillaires et/ou mandibulaires. Conclusions 1/ La faible qualite de vie orale ressentie par les patients contraste avec un etat bucco-dentaire plutot satisfaisant. 2/ Les exostoses maxillaires et mandibulaires pourraient etre un point d’appel specifique pour le diagnostic de l’acromegalie. 3/ Ces resultats sont en faveur d’un suivi dentaire des patients acromegales identique a celui de la population generale.
Published: 2018
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11. Spermiogenèse : l’acétylation des histones déclenche la reprogrammation du génome mâle

Author: Hervé Lejeune, Sandrine Curtet, Jean-Pierre Siffroi, Célia Ravel, Sophie Rousseaux, C. Derobertis, C. Jimenez, Cécile Caron, Anne-Laure Vitte, I. Aknin-Seifer, J. Thevenon, Rachel Levy, Jonathan Gaucher, Saadi Khochbin, A. K. Faure, K. Mc Elreavey, and Sylviane Hennebicq
Subjects: Mutation, Obstetrics and Gynecology, General Medicine, Biology, medicine.disease_cause, Genome, Bromodomain, Chromatin, Cell biology, chemistry.chemical_compound, Histone, Reproductive Medicine, chemistry, medicine, biology.protein, Epigenetics, Reprogramming, DNA
Abstract: During their post-meiotic maturation, male germ cells undergo an extensive reorganization of their genome, during which histones become globally hyperacetylated, are then removed and progressively replaced by transition proteins and finally by protamines. The latter are known to tightly associate with DNA in the mature sperm cell. Although this is a highly conserved and fundamental biological process, which is a necessary prerequisite for the transmission of the male genome to the next generation, its molecular basis remains mostly unknown. We have identified several key factors involved in this process, and their detailed functional study has enabled us to propose the first model describing molecular mechanisms involved in post-meiotic male genome reprogramming. One of them, Bromodomain Testis Specific (BRDT), has been the focus of particular attention since it possesses the unique ability to specifically induce a dramatic compaction of acetylated chromatin. Interestingly, a mutation was found homozygous in infertile men which, according to our structural and functional studies, disrupts the function of the protein. A combination of molecular structural and genetic approaches has led to a comprehensive understanding of new major actors involved in the male genome reprogramming and transmission.
Published: 2009
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12. Epigenetic reprogramming of the male genome during gametogenesis and in the zygote

Author: E. Escoffier, Cécile Caron, Saadi Khochbin, Sophie Rousseaux, J. Thevenon, and Nicolas Reynoird
Subjects: Male, Zygote, Embryonic Development, Models, Biological, Genome, Gametogenesis, Epigenesis, Genetic, Histones, DNA Packaging, Animals, Humans, Epigenetics, Pericentric heterochromatin, Histone Acetyltransferases, Epigenesis, Genetics, biology, Nuclear Proteins, Obstetrics and Gynecology, Acetylation, Chromatin Assembly and Disassembly, Spermatozoa, Chromatin, Meiosis, Histone, Reproductive Medicine, biology.protein, Reprogramming, Developmental Biology
Abstract: During post-meiotic maturation, male germ cells undergo a formidable reorganization and condensation of their genome. During this phase most histones are globally acetylated and then replaced by sperm-specific basic proteins, named protamines, which compact the genome into a very specific structure within the sperm nucleus. Several studies suggest that this sperm-specific genome packaging structure conveys an important epigenetic message to the embryo. This paper reviews what is known about this fundamental, yet poorly understood, process, which involves not only global changes of the structure of the haploid genome, but also localized specific modifications of particular genomic regions, including pericentric heterochromatin and sex chromosomes. After fertilization, the male genome undergoes a drastic decondensation, and rapidly incorporates new histones. However, it remains different from the maternal genome, bearing specific epigenetic marks, especially in the pericentric heterochromatin region. The functional implications of male post-meiotic and post-fertilization genome reprogramming are not well known, but there is experimental evidence to show that it affects early embryonic development.
Published: 2008
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13. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping

Author: J S, Amos, L, Huang, J, Thevenon, A, Kariminedjad, C L, Beaulieu, A, Masurel-Paulet, H, Najmabadi, Z, Fattahi, M, Beheshtian, S H, Tonekaboni, S, Tang, K L, Helbig, W, Alcaraz, J-B, Rivière, L, Faivre, A M, Innes, R R, Lebel, and K M, Boycott
Subjects: Male, Models, Molecular, Adolescent, Genotype, Mutation, Missense, RNA-Binding Proteins, Genes, Recessive, Sequence Analysis, DNA, Syndrome, Severity of Illness Index, Phenotype, Protein Domains, Intellectual Disability, Humans, Exome, Female, Genetic Predisposition to Disease, Child
Abstract: THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment.
Published: 2016

14. Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis

Author: A-L, Bruel, A, Masurel-Paulet, J-B, Rivière, Y, Duffourd, D, Lehalle, C, Bensignor, F, Huet, J, Borgnon, F, Roucher, P, Kuentz, J-F, Deleuze, C, Thauvin-Robinet, L, Faivre, and J, Thevenon
Subjects: Homeodomain Proteins, Male, Developmental Disabilities, Homozygote, Mice, Phenotype, Intellectual Disability, Mutation, Scrotum, Animals, Humans, Abnormalities, Multiple, Exome, Child, Frameshift Mutation
Abstract: We report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remarkable hallmarks. Four cases from the literature were reported with features suggestive of a similar and recognizable clinical entity. We hypothesize that MAB21L1 should be the culprit gene in these patients.
Published: 2016

15. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease

Author: L, Allou, S, Julia, D, Amsallem, S, El Chehadeh, L, Lambert, J, Thevenon, Y, Duffourd, A, Saunier, P, Bouquet, S, Pere, A, Moustaïne, L, Ruaud, V, Roth, P, Jonveaux, and C, Philippe
Subjects: Male, Adolescent, High-Throughput Nucleotide Sequencing, Infant, Protein Serine-Threonine Kinases, Genetic Heterogeneity, Phenotype, Codon, Nonsense, Child, Preschool, Mutation, Kv1.2 Potassium Channel, Rett Syndrome, Guanine Nucleotide Exchange Factors, Humans, Exome, Female
Abstract: Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.
Published: 2016

16. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

Author: J, Thevenon, Y, Duffourd, A, Masurel-Paulet, M, Lefebvre, F, Feillet, S, El Chehadeh-Djebbar, J, St-Onge, A, Steinmetz, F, Huet, M, Chouchane, V, Darmency-Stamboul, P, Callier, C, Thauvin-Robinet, L, Faivre, and J B, Rivière
Subjects: Adult, Male, Epilepsy, Adolescent, Diagnostic Tests, Routine, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Cohort Studies, Young Adult, Neurodevelopmental Disorders, Child, Preschool, Intellectual Disability, Humans, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Child
Abstract: The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.
Published: 2015

17. Homozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities

Author: C, Thauvin-Robinet, L, Duplomb-Jego, F, Limoge, D, Picot, A, Masurel, B, Terriat, C, Champilou, D, Minot, J, St-Onge, P, Kuentz, Y, Duffourd, J, Thevenon, J-B, Rivière, and L, Faivre
Subjects: Male, Adolescent, Learning Disabilities, Homozygote, Genetic Variation, High-Throughput Nucleotide Sequencing, Membrane Proteins, Syndrome, Megalencephaly, Pedigree, Consanguinity, Humans, Abnormalities, Multiple, Exome, Female, Eye Abnormalities, Carrier Proteins, Growth Disorders
Abstract: The acidic fibroblast growth factor (FGF) intracellular binding protein (FIBP) interacts directly with the fibroblast growth factor FGF1. Although FIBP is known to be implicated in the FGF signaling pathway, its precise function remains unclear. Gain-of-function variants in several FGF receptors (FGFRs) are implicated in a wide spectrum of growth disorders from achondroplasia to overgrowth syndromes. In a unique case from a consanguineous union presenting with overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning disabilities, exome sequencing identified a homozygous nonsense FIBP variant. The patient's fibroblasts exhibit FIBP cDNA degradation and an increased proliferation capacity compared with controls. The phenotype defines a new multiple congenital abnormalities (MCA) syndrome, overlapping with the heterogeneous group of overgrowth syndromes with macrocephaly. The different clinical features can be explained by the alteration of the FGFR pathway. Taken together, these results suggest the implication of FIBP in a new autosomal recessive MCA.
Published: 2015

18. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management

Author: M, Avila, D A, Dyment, J V, Sagen, J, St-Onge, U, Moog, B H Y, Chung, S, Mo, S, Mansour, A, Albanese, S, Garcia, D O, Martin, A A, Lopez, T, Claudi, R, König, S M, White, S L, Sawyer, J A, Bernstein, L, Slattery, R K, Jobling, G, Yoon, C J, Curry, M L, Merrer, B L, Luyer, D, Héron, M, Mathieu-Dramard, P, Bitoun, S, Odent, J, Amiel, P, Kuentz, J, Thevenon, M, Laville, Y, Reznik, C, Fagour, M-L, Nunes, D, Delesalle, S, Manouvrier, O, Lascols, F, Huet, C, Binquet, L, Faivre, J-B, Rivière, C, Vigouroux, P R, Njølstad, A M, Innes, C, Thauvin-Robinet, CHU 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), Children's hospital of Eastern Ontario Research Institute, University of Bergen (UiB), Haukeland University Hospital, Human Genetics Institute, Heidelberg University, Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, St George's Hospital, INGEMM, Instituto de Genética Médica y Molecular, IDIPAZ-Hospital Universitario La Paz, Instituto de Salud Carlos III [Madrid] (ISC), Hospital Central de la Cruz Roja San Jose y Santa Adela, University Hospital Puerta de Hierro, Madrid, Bodø University College, Humangenetik, Universitätsklinikum Frankfurt, University of Frankfurt, University of Melbourne, Victorian Clinical Genetics Services, Stanford University, The Hospital for sick children [Toronto] (SickKids), University of California [San Francisco] (UCSF), University of California, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CH Le Havre, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], 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)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], CHU Amiens-Picardie, Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], 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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), 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, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Bordeaux [Bordeaux], CH Valenciennes, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), University of Calgary, Financial support was from the Regional Council of Burgundy and the Care4Rare Canada Consortium was funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’sHospital of Eastern Ontario Foundation. DAD is the recipient of a CIHR Clinical Investigator award from the Institute of Genetics. PRN was supported in part by grants from the Research Council of Norway, The University of Bergen, an ERC Advanced Grant, Helse Vest and the KG Jebsen Foundation., SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], 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 de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, University of Bergen (UIB), Instituto de Salud Carlos III (ISC), Stanford University [Stanford], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Service de neuropédiatrie [Trousseau], Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Recherche Clinique, Université Joseph Fourier - Grenoble 1 (UJF)-Centre de Recherche en Nutrition Humaine Rhône - Alpes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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, University of Bergen ( UIB ), The University of Hong Kong ( HKU ), Instituto de Salud Carlos III (ISCIII) - Spain RDR - CIBERER, University of California [San Francisco] ( UCSF ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), 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 ), 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 ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre de Recherche en Nutrition Humaine Rhône - Alpes, 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 ), Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), 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 ), University of California [San Francisco] (UC San Francisco), University of California (UC), 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 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), 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]), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)
Subjects: short stature, lipoatrophy, intrauterine growth restriction, [ SDV ] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV]Life Sciences [q-bio], Diabetes, PIK3R1 gene, Insulin Resistance, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, SHORT syndrome
Abstract: International audience; SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
Published: 2015
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19. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Author: J, Piard, B, Aral, P, Vabres, M, Holder-Espinasse, A, Mégarbané, S, Gauthier, V, Capra, G, Pierquin, P, Callier, C, Baumann, L, Pasquier, G, Baujat, L, Martorell, A, Rodriguez, A F, Brady, F, Boralevi, M A, González-Enseñat, M, Rio, C, Bodemer, N, Philip, M-P, Cordier, A, Goldenberg, B, Demeer, M, Wright, E, Blair, E, Puzenat, P, Parent, Y, Sznajer, C, Francannet, N, DiDonato, O, Boute, V, Barlogis, O, Moldovan, D, Bessis, C, Coubes, M, Tardieu, V, Cormier-Daire, A B, Sousa, J, Franques, A, Toutain, M, Tajir, S C, Elalaoui, D, Geneviève, J, Thevenon, J-B, Courcet, J-B, Rivière, C, Collet, N, Gigot, L, Faivre, C, Thauvin-Robinet, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire de Génétique Chromosomique et Moléculaire [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), Service de Dermatologie (CHU de Dijon), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Saint-Joseph de Beyrouth (USJ), 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), Laboratoire de cytogénétique (CHU de Dijon), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de dermatologie [CHU Necker], 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), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Clermont-Ferrand, Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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), 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)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Herrada, Anthony, CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, Comparative Genomic Hybridization, Rothmund-Thomson syndrome, RECQL4, Adolescent, Genotype, RecQ Helicases, poikiloderma, Facies, Infant, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Consanguinity, Craniosynostoses, Radius, Young Adult, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Mutation, Humans, Female, Baller-Gerold syndrome, Child
Abstract: International audience; Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.
Published: 2015
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20. Quel profil des patients métastatiques hormonosensibles en 2016 ? Enquête descriptive de la pratique et de la prise en charge en France

Author: A. De La Taille, Christophe Massard, M. Bolla, and J. Thevenon
Subjects: Gynecology, medicine.medical_specialty, business.industry, Urology, medicine, business
Abstract: Objectifs Le cancer metastatique de la prostate est une maladie tres heterogene pour laquelle plusieurs facteurs pronostiques ont ete identifies. En France, si l’incidence et l’epidemiologie de la maladie sont etudiees, il existe en revanche peu de donnees specifiques sur les patients metastatiques hormonosensibles. Le but cette enquete descriptive est de decrire la prise en charge de ces patients en pratique quotidienne. Methodes L’enquete a ete conduite aupres de 98 medecins participants (44 urologues et 54 oncologues medicaux et/ou radiotherapeutes) entre novembre et decembre 2016, via un cahier de recueil (questionnaire de 2 pages) reprenant l’historique de la maladie depuis son diagnostic initial. Au total, 984 cas patient ont ete recueillis, pour lesquels un diagnostic de cancer de la prostate metastatique a ete pose entre le 1er janvier 2014 et le 31 decembre 2015, qu’il s’agisse d’un primo-diagnostic (cancer de la prostate de novo metastatique) ou d’un cancer de la prostate en recidive metastatique. Un focus particulier a ete realise chez les patients diagnostiques metastatiques d’emblee. Resultats Cinquante-six pour cent des patients (n = 549) ont ete diagnostiques en phase metastatique a partir d’un dosage du PSA (77 %), de douleurs ou d’evenements osseux (50 %). Dans plus de 70 % des cas, l’urologue a gere la prise en charge du patient. L’âge moyen etait de 69,4 ans (min 41 ; max 93), 61 % des patients avaient un score de Gleason ≥ 8. Une alteration de l’etat general etait presente dans 26 % des cas (ECOG 2 + ) et une comorbidite dans 69 %. Quatre-vingt-quinze pour cent presentaient de multiples metastases osseuses, 14 % viscerales. 77 % etaient classes « haut volume » (metastases viscerales ou + de 3 lesions osseuses) et 54 % sont « haut risque » (2 parmi Gleason ≥ 8 et criteres haut volume). Tous les patients ont recu un agoniste LHRH dont 17 % en association avec docetaxel en 2015. Conclusion L’urologue reste l’acteur cle de la prise en charge des patients metastatiques en pratique quotidienne. Ces patients restent des patients âges avec des co-morbidites importantes et une charge tumorale elevee. Les nouvelles recommandations sur l’utilisation de la chimiotherapie precoce par docetaxel sont progressivement adoptees.
Published: 2017
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21. Measuring The Intensity Of Care Coordination For Blood Cancer Patients In France

Author: T. Kanouni, J Thevenon, J Chevalier, G. Cartron, G. Mercier, and C. Duflos
Subjects: Blood cancer, medicine.medical_specialty, business.industry, Health Policy, Public Health, Environmental and Occupational Health, medicine, Intensive care medicine, business, Intensity (physics)
Published: 2017
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22. Using Observational Data From Registry In Cost-Effectiveness Evaluation of Metastatic Castration Resistant Prostate Cancer In France

Author: J Thevenon, C Capone, H Leleu, E Klumper, J Chevalier, Robert Wapenaar, and L de Beaucoudrey
Subjects: Oncology, medicine.medical_specialty, Prostate cancer, business.industry, Cost effectiveness, Health Policy, Internal medicine, Public Health, Environmental and Occupational Health, Medicine, Observational study, Castration resistant, business, medicine.disease
Published: 2017
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23. Syndrome MIRAGE : données cliniques et biologiques chez 8 patients mutés pour le gène SAMD9

Author: J. Thevenon, M. Gerard, Raja Brauner, Graziella Pinto, V. Ribault, Pierre-Simon Jouk, Florence Roucher-Boulez, V. Tardy-Guidollet, C. Chalouhi, C. Ben Signor, D. Mallet-Motak, Y. Morel, P. Bretones, and D. Kariyawasam
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Objectifs Le syndrome myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) est du a des mutations de novo du gene SAMD9. L’objectif etait de rechercher des mutations dans une cohorte de patients avec retard de croissance in utero (RCIU), insuffisance surrenale (IS) et/ou anomalie du developpement genitosexuel (DSD) et de caracteriser leur phenotype gonadique et surrenalien. Methode Sequencage Sanger de SAMD9 chez 20 patients. Resultats Le syndrome de 8 patients a pu etre explique par des mutations faux-sens SAMD9 (4 nouvelles). Celui-ci etait generalement complet avec chez certains des signes additionnels : reins hypoplasiques, detresse respiratoire. Les 8 etaient 46,XY DSD avec des degres variables de masculinisation. Un seul a ete eleve en garcon. Aucun residu mullerien n’a pu etre detecte malgre une AMH basse. Dans la plupart des cas, les gonades etaient ectopiques avec une testosterone basse. L’IS etait neonatale avec des taux bas de steroides, excepte les taux de D4-androstenedione et de 11-desoxycortisol suggerant une atteinte des CYP450 de type II de la steroidogenese. L’issue est rapidement fatale in utero ou dans la premiere annee de vie, mais une patiente est encore en vie (14 ans) et n’a aucun signe d’IS. Conclusions Il est important de sequencer le gene SAMD9 face a l’association RCIU, IS et/ou DSD, syndrome polymalformatif. Colliger ces cas avec les donnees cliniques et biologiques, nous permettra une meilleure comprehension du role de ce gene dans le developpement surrenalien et gonadique.
Published: 2017
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24. CA-087: Qualité de vie liée à la santé orale des patients diabétiques de type 1

Author: B. Roche, M. Batisse-Lignier, Igor Tauveron, L. Devoize, J. Thevenon, and F. Desbiez
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine, General Medicine
Abstract: Introduction Les repercussions buccales du diabete sont nombreuses et sont principalement representees par une hyposialie, des hyperplasie(s) gingivale(s), une susceptibilite a la carie et a diverses infections, notamment la maladie parodontale. Selon l'ADA, la parodontite est ainsi la 6 e complication du diabete. De Pinho AM. et al (2012) ont montre que 60 % des diabetiques sont insatisfaits de leur qualite de vie. Peu d'etudes relatent la qualite de la vie orale des diabetiques. Materiels et Methodes L'objectif de cette etude etait d'evaluer les repercussions du diabete de type 1 sur la qualite de vie liee a la sante orale, a l'aide d'un autoquestionnaire, le General Oral Health Assessment Index (GOHAI, 12 items scores, refletant une bonne satisfaction de 57 a 60, une satisfaction moyenne de 51 a 56 et une satisfaction faible de 50 et moins). Les malades inclus avaient entre 18 et 50 ans, sans perte d'autonomie et comprenaient le francais. Les femmes enceintes ont ete exclues (troubles gravidiques de la sphere orale). Les donnees medicales ont ete recueillies. L'analyse statistique a ete realisee grâce au logiciel Graph Pad Prism v5. Resultats 104 dossiers complets ont ete retenus. La moyenne du GOHAI etait de 53.46 ± 6,78, donnant une qualite de vie orale moyenne et indiquant la presence de troubles bucco-dentaires. Aucune correlation n'a ete trouvee entre anciennete du diabete et GOHAI ; Il a ete trouve une correlation inverse entre taux d'HbA 1c et GOHAI (r = − 0,3351, p vs 54.47 ± 0,69, p Discussions On retrouve des similarites avec les etudes de Glavind et al, (1969) ou celle d'Abikshyeet P et al, (2012) qui ont note une association entre la survenue de problemes dentaires et les complications liees au diabete. De meme, le diabete n'est pas un facteur declenchant de la maladie parodontale ; il est par contre un facteur aggravant. L'utilisation du questionnaire GOHAI pour le non specialiste pourrait etre utile dans la detection de problemes bucco-dentaires.
Published: 2016
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25. What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

Author: F, Coron, T, Rousseau, G, Jondeau, E, Gautier, C, Binquet, L, Gouya, V, Cusin, S, Odent, Y, Dulac, H, Plauchu, P, Collignon, M-A, Delrue, B, Leheup, L, Joly, F, Huet, J, Thevenon, G, Mace, C, Cassini, C, Thauvin-Robinet, J E, Wolf, N, Hanna, P, Sagot, C, Boileau, L, Faivre, Centre de référence MARFAN, Hôpital Bichat, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, 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 ), Service de Génétique, Hôtel Dieu, Centre Hospitalier de toulon, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), 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), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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 )
Subjects: Adult, Male, Parents, Adolescent, Genetics, Medical, [SDV]Life Sciences [q-bio], Middle Aged, Marfan Syndrome, Young Adult, Prenatal Diagnosis, Surveys and Questionnaires, Humans, Female, France, Preimplantation Diagnosis
Abstract: International audience; Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. Two different questionnaires were produced. Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.
Published: 2012
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26. [Spermiogenesis: histone acetylation triggers male genome reprogramming]

Author: S, Rousseaux, J, Gaucher, J, Thevenon, C, Caron, A-L, Vitte, S, Curtet, C, Derobertis, A-K, Faure, R, Levy, I, Aknin-Seifer, C, Ravel, J-P, Siffroi, K, Mc Elreavey, H, Lejeune, C, Jimenez, S, Hennebicq, and S, Khochbin
Subjects: Histones, Male, Meiosis, Humans, Nuclear Proteins, Acetylation, Spermatogenesis, Spermatozoa, Chromatin, Infertility, Male, Epigenesis, Genetic
Abstract: During their post-meiotic maturation, male germ cells undergo an extensive reorganization of their genome, during which histones become globally hyperacetylated, are then removed and progressively replaced by transition proteins and finally by protamines. The latter are known to tightly associate with DNA in the mature sperm cell. Although this is a highly conserved and fundamental biological process, which is a necessary prerequisite for the transmission of the male genome to the next generation, its molecular basis remains mostly unknown. We have identified several key factors involved in this process, and their detailed functional study has enabled us to propose the first model describing molecular mechanisms involved in post-meiotic male genome reprogramming. One of them, Bromodomain Testis Specific (BRDT), has been the focus of particular attention since it possesses the unique ability to specifically induce a dramatic compaction of acetylated chromatin. Interestingly, a mutation was found homozygous in infertile men which, according to our structural and functional studies, disrupts the function of the protein. A combination of molecular structural and genetic approaches has led to a comprehensive understanding of new major actors involved in the male genome reprogramming and transmission.
Published: 2009

27. Effect of multiple intravenous pamidronate courses in Paget's disease of bone

Author: A, Trombetti, M, Arlot, J, Thevenon, B, Uebelhart, and P J, Meunier
Subjects: Adult, Aged, 80 and over, Male, Diphosphonates, Anti-Inflammatory Agents, Pain, Pamidronate, Middle Aged, Osteitis Deformans, Radiography, Injections, Intravenous, Humans, Female, Joint Diseases, Bone Demineralization, Pathologic, Aged, Retrospective Studies
Abstract: Pamidronate is a bisphosphonate whose short-term biological efficacy in Paget's disease of bone was convincingly established many years ago. A less well studied area is the efficacy of pamidronate in slowing disease progression and in preventing and treating complications.We conducted an uncontrolled retrospective study of 79 Paget's disease patients given multiple intravenous pamidronate courses over a mean period of 45 +/- 19 months. The pamidronate dose per course was 180 mg, usually given over three days. The disease was severe and in some cases had proved refractory to other medications. Reasons for pamidronate therapy were pain or other subjective symptoms; established bone, joint, or nervous system complications; or prevention or these complications in patients with involvement of high-risk sites.Bone and joint pain improved under therapy, and in 78% of cases the outcome in terms of complication treatment and/or prevention was favorable. An important finding was waning of the clinical and biological effects of pamidronate as the number of courses increased. Fourteen percent of patients developed resistance to pamidronate, which seemed more closely related to disease extension than to focal lesion activity.These data suggest that a prompt return to normal of laboratory markers, most notably total alkaline phosphatase, should be sought, if needed by using higher doses than in our study.
Published: 1999

28. Two-year study of endemic enteric pathogens associated with acute diarrhea in New Caledonia

Author: H. Dubourdieu, M. Morillon, R. Costa, J Thevenon, E. Begaud, and Yves Germani
Subjects: Microbiology (medical), Adult, Diarrhea, Male, Rotavirus, Adolescent, medicine.disease_cause, Campylobacter jejuni, Rotavirus Infections, Microbiology, Feces, fluids and secretions, New Caledonia, parasitic diseases, medicine, Animals, Humans, Shigella, Intestinal Diseases, Parasitic, Yersinia enterocolitica, Child, Escherichia coli, Aged, Protozoan Infections, biology, Bacteria, Incidence, Age Factors, Eukaryota, Bacterial Infections, Clostridium difficile, Clostridium perfringens, Middle Aged, biology.organism_classification, Virology, Child, Preschool, Acute Disease, Female, Seasons, medicine.symptom, Water Microbiology, Research Article
Abstract: A longitudinal study of diarrheal disease among patients of all ages with acute diarrhea was carried out in New Caledonia from January 1990 to December 1991. Stool samples from 2,088 diarrheal patients were examined for parasites, rotavirus, and bacterial pathogens. Potential sources of contamination (drinking water, seawater and bovine and porcine feces) were investigated. One or more enteric pathogens were identified in 41.8 and 40.6% of the persons with diarrhea, in 1990 and 1991, respectively. Salmonella spp., Shigella spp., HEp-2 cell adherent Escherichia coli (diffuse adherent and enteroaggregative), enteropathogenic E. coli (EPEC) (EPEC adherence factor-positive strains belonging to classical serotypes), localized adherent E. coli (non-EPEC), and enterotoxigenic E. coli were the frequently identified enteropathogenic bacteria. Other major enteropathogens were Entamoeba histolytica and Giardia lamblia. Campylobacter jejuni, Clostridium difficile, Clostridium perfringens, Yersinia enterocolitica, and rotavirus were isolated from only a few patients. No Vibrio spp., Aeromonas spp., Plesiomonas spp., Shiga-like-toxin-producing E. coli, enterohemorrhagic E. coli, or enteroinvasive E. coli were identified. Shiga-like toxin I-producing E. coli were present in adult bovines and calves, and heat-stable enterotoxin II-producing enterotoxigenic E. coli were found in pigs.
Published: 1994

29. [Infection by avian chlamydiosis in breeding pigeons in New Caledonia]

Author: J, Thevenon, D, Rantoen, D, Carton, R, Costa, and D, Trap
Subjects: Male, Bird Diseases, Complement Fixation Tests, Breeding, Psittacosis, Antibodies, Bacterial, Chlamydophila psittaci, New Caledonia, Quarantine, Prevalence, Animals, Female, Columbidae, Yolk Sac
Abstract: An epidemiological survey on avian chlamydiosis, carried out by serological probing in 8 pigeon breeders representative of New Caledonian livestock, combined with bacteriological research on pigeon organs and droppings was set up in New Caledonia in order to determine the prevalence rate of this infection and to adapt sanitary regulations concerning pigeon imports. All sera collected (230) were analysed by complement fixation test (CFT). The organs were diluted in sucrose solution, then stored frozen (-70 degrees C), until inoculation of the yolk-sac of 3 6-8-day-old embryonated eggs (2 blind passages). Yolk-sac smears stained according to the Gimenez method were made in order to detect intracellular chlamydial organisms. Seventeen sera out of 230 were found to be positive, ie 7.4% of the test sample (confidence interval to 95% = 4.0 to 10.8%). The carrier pigeons were significantly more infected (17.8%) than pigeons of other breeds in New Caledonia. These results resulted in the sanitary authorities easing restrictions on imports of seropositive pigeons by imposing a 45-day compulsory quarantine with daily administration of chlortetracycline at the rate of 150 mg per 1 of drinking water.
Published: 1992

30. [Sarcoidosis with clinically isolated mediastinal adenopathy; diagnosis confirmed by biopsy of inguinalright pre-scalenic lymph nodes]

Author: P, MONNET and J, THEVENON
Subjects: Sarcoidosis, Biopsy, Humans, Infant, Lymph Nodes, Child, Lymphatic Diseases
Published: 1959

31. [Chelating agents in dermatology; first trials]

Author: H, THIERS, D, COLOMB, R, PATET, and J, THEVENON
Subjects: Humans, Dermatology, Skin Diseases, Edetic Acid, Chelating Agents
Published: 1957

32. [Hydrocolpos of the young infant]

Author: P, MONNET, J, MARION, J, DUBOIS, J, THEVENON, and C, MOREL
Subjects: Vagina, Vaginal Diseases, Infant, Newborn, Humans, Infant, Disease, Female, Hydrocolpos, Infant, Newborn, Diseases
Published: 1959

33. [Petechiae of the soft palate in infectious mononucleosis; semeiological value]

Author: P, MONNET, J, GAUTHIER, and J, THEVENON
Subjects: Palate, Humans, Infectious Mononucleosis, Palate, Soft, Purpura
Published: 1959

34. [Neonatal total respiratory paralysis csecondary to an obsterical injury. Possibility of respiratory resuscitation in the newborn]

Author: P, SEDALLIAN, M, GIROUD, J, THEVENON, P, VINCENT, and MARTIN
Subjects: Pregnancy, Resuscitation, Infant, Newborn, Humans, Respiratory Paralysis
Published: 1959

35. [Anemic syndrome of the Jaksch Hayem Luzet type in a young infant]

Author: P, MONNET and J, THEVENON
Subjects: Tracheophyta, Humans, Infant, Anemia, Anemia, Myelophthisic, Syndrome, Child
Published: 1959

36. [Chylous cysteic lymphangioma of the mesentery]

Author: F, Freycon, P, Mollard, J, Thevenon, J L, Bertrand, and M, Jeune
Subjects: Male, Mesenteric Cyst, Lymphangioma, Child, Preschool, Humans, Chyle, In Vitro Techniques
Published: 1966

37. An Extended Phenotype of PPP1R13L Cardiocutaneous Syndrome.

Author: Coudert A, Thevenon J, Testard Q, Satre V, Harbuz R, Bouvagnet P, Rabattu PY, Coutton C, and Le Tanno P
Abstract: Dilated cardiomyopathy (DCM) is a rare disease in children and a leading cause of heart failure. There are numerous causes of DCM including genetic causes leading to isolated or syndromic presentations, with a wide variety of implicated genes. Among them, PPP1R13L is associated with a recessive syndrome leading to cardiac anomalies with skin, teeth, and hair abnormalities. Fifteen patients have been described so far. We report a patient born to unrelated parents with early-onset and progressive DCM, skin appendage anomalies, and an anorectal anomaly. Her late brother shared the same phenotype. Exome sequencing revealed biallelic loss-of-function (LoF) variants of PPP1R13L in the proband, also present in her affected brother. To our knowledge, anorectal anomalies had never been previously described in PPP1R13L mutated individuals. As exome sequencing did not identify any other candidate variant to explain this malformation, this feature may expand the phenotype of PPP1R13L LoF disorder., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Published: 2024
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38. Description of Feelings, Perception, and Experience Before and After Switching from IV Daratumumab to the SC Form: A Mixed-Method, Cross-Sectional Survey in Multiple Myeloma Patients in Europe.

Author: Magarotto V, Thevenon J, Morgan K, Ten Seldam S, Iraqi W, Guillaume X, Leclerc M, Graziani-Taugeron C, Rault B, and Horchi D
Abstract: Purpose: To provide real-world data on patient perceptions and experiences with subcutaneous (SC) versus intravenous (IV) daratumumab., Patients and Methods: This was a cross-sectional, mixed-method (qualitative/quantitative) survey conducted in France, Germany, Spain and the United Kingdom involving multiple myeloma (MM) patients who switched from IV to SC daratumumab in the last 12 months (qualitative phase) or 24 months (quantitative phase [26 months in the UK]) prior to enrollment in the study., Results: Nine patients (mean age 65 years) participated in the qualitative phase and 113 patients (mean age 65.1 years) in the quantitative phase. Qualitative study results provided insights for the quantitative study and highlighted the benefits of switching from daratumumab IV to daratumumab SC as an improvement and a satisfactory change in patients' treatment journey. Quantitative survey showed that patients were significantly less anxious, stressed and nervous before SC injections than IV infusions (mean score: 1.3, 1.1, 1.4 versus 2.1, 2.0, 2.0 respectively, p<0.001), and significantly more reassured, ready/well-prepared, usual self and relieved (mean score: 3.8, 4.3, 3.7, 3.6 versus 3.0, 3.6, 3.1, 3.0 respectively, p<0.001). Immediately after SC first injection, 96.5% patients were feeling well or very well versus 77.9% immediately after IV first infusion (p<0.001). 97.3% patients were satisfied with their SC treatment versus 89.4% for the IV injection (p<0.001). Patients spent significantly less time in hospital for an SC injection of daratumumab than for an IV infusion, 1.5 hours and 5.0 hours respectively (p<0.001). In the UK, the differences between the two administration forms were less visible, likely because of confounding factors including a longer time passed since the switch from the IV to the SC form and administration of the survey., Conclusion: In line with results from other studies, the SC form of daratumumab had less impact on patients' emotional burden than the IV form., Competing Interests: Julien Thevenon, Wafae Iraqi and Valeria Magarotto are employees/ shareholders of Janssen. Mrs Valeria Magarotto reports being an employee of Johnson and Johnson outside the submitted work. Xavier Guillaume, Dahbia Horchi, Bleuenn Rault, Marjorie Leclerc and Claire Graziani Taugeron are employees of Oracle France. Kate Morgan and Silene Ten Seldam are employees of Myeloma Patient Europe (MPE) which receives funding from the following sponsors: AbbVie, Amgen, Alexion, BeiGene, Binding Site, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline Therapeutics, Takeda, Sebia, Prothena, SkylineDx, Sandoz. Kate Morgan has been a member of the Janssen Global MM Collaboration Council since 2021. The authors report no other conflicts of interest in this work., (© 2024 Magarotto et al.)
Published: 2024
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39. X-linked transient antenatal Bartter syndrome related to MAGED2 gene: Enriching the phenotypic description and pathophysiologic investigation.

Author: Buffet A, Filser M, Bruel A, Dard R, Quibel T, Dubucs C, Kwon T, Le Tanno P, Thevenon J, Ziegler A, Allard L, Guigonis V, Roux JJ, Heidet L, Rougeulle C, Boyer O, Vargas-Poussou R, and Hureaux M
Abstract: Purpose: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women., Methods: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples., Results: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases, and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%), and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women., Conclusion: This work enriches the phenotypic and genetic description of this recently described disease and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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40. Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Author: Tusseau M, Eyries M, Chatron N, Coulet F, Guichet A, Colin E, Demeer B, Maillard H, Thevenon J, Lavigne C, Saillour V, Paris C, De Sainte Agathe JM, Pujalte M, Guilhem A, Dupuis-Girod S, and Lesca G
Subjects: Humans, Mutation, Endoglin genetics, Base Sequence, Chromosomes, Human, Pair 9 genetics, Activin Receptors, Type II genetics, Telangiectasia, Hereditary Hemorrhagic diagnosis, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology
Abstract: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2024
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41. Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases.

Author: Racine C, Denommé-Pichon AS, Engel C, Tran Mau-Them F, Bruel AL, Vitobello A, Safraou H, Sorlin A, Nambot S, Delanne J, Garde A, Colin E, Moutton S, Thevenon J, Jean-Marçais N, Willems M, Geneviève D, Pinson L, Perrin L, Laffargue F, Lespinasse J, Lacaze E, Molin A, Gerard M, Lambert L, Benigni C, Patat O, Bourgeois V, Poe C, Chevarin M, Couturier V, Garret P, Philippe C, Duffourd Y, Faivre L, and Thauvin-Robinet C
Subjects: Humans, Retrospective Studies, Phenotype, Exome Sequencing, Rare Diseases genetics, Intellectual Disability diagnosis, Intellectual Disability genetics
Abstract: Purpose: Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID)., Methods: From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018)., Results: MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%)., Conclusion: MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2023
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42. Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Author: Liu Z, Xin B, Smith IN, Sency V, Szekely J, Alkelai A, Shuldiner A, Efthymiou S, Rajabi F, Coury S, Brownstein CA, Rudnik-Schöneborn S, Bruel AL, Thevenon J, Zeidler S, Jayakar P, Schmidt A, Cremer K, Engels H, Peters SO, Zaki MS, Duan R, Zhu C, Xu Y, Gao C, Sepulveda-Morales T, Maroofian R, Alkhawaja IA, Khawaja M, Alhalasah H, Houlden H, Madden JA, Turchetti V, Marafi D, Agrawal PB, Schatz U, Rotenberg A, Rotenberg J, Mancini GMS, Bakhtiari S, Kruer M, Thiffault I, Hirsch S, Hempel M, Stühn LG, Haack TB, Posey JE, Lupski JR, Lee H, Sarn NB, Eng C, Gonzaga-Jauregui C, Zhang B, and Wang H
Subjects: Male, Humans, Protein Phosphatase 1 genetics, Glucose, Glycogen, Intellectual Disability genetics, Intellectual Disability complications, Autism Spectrum Disorder genetics, Autistic Disorder genetics, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders complications
Abstract: Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2023
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43. The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

Author: Levaillant L, Bouhours-Nouet N, Illouz F, Amsellem Jager J, Bachelot A, Barat P, Baron S, Bensignor C, Brac De La Perriere A, Braik Djellas Y, Caillot M, Caldagues E, Campas MN, Caquard M, Cartault A, Cheignon J, Decrequy A, Delemer B, Dieckmann K, Donzeau A, Doye E, Fradin M, Gaudillière M, Gatelais F, Gorce M, Hazart I, Houcinat N, Houdon L, Ister-Salome M, Jozwiak L, Jeannoel P, Labarthe F, Lacombe D, Lambert AS, Lefevre C, Leheup B, Leroy C, Maisonneuve B, Marchand I, Marquant E, Muszlak M, Pantalone L, Pochelu S, Quelin C, Radet C, Renoult-Pierre P, Reynaud R, Rouleau S, Teinturier C, Thevenon J, Turlotte C, Valle A, Vierge M, Villanueva C, Ziegler A, Dieu X, Bouzamondo N, Rodien P, Prunier-Mirebeau D, and Coutant R
Subjects: Humans, Mutation, Genomics, High-Throughput Nucleotide Sequencing, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism genetics
Abstract: Introduction: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH., Methods: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded., Results: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L., Conclusion: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
Published: 2023
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44. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.

Author: Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, Kurolap A, Henig NZ, Fatih JM, Herman I, Du H, Mitani T, Becker L, Rathkolb B, Gerlini R, Seisenberger C, Marschall S, Hunter JV, Gerard A, Heidlebaugh A, Challman T, Spillmann RC, Jhangiani SN, Coban-Akdemir Z, Lalani S, Liu L, Revah-Politi A, Iglesias A, Guzman E, Baugh E, Boddaert N, Rondeau S, Ormieres C, Barcia G, Tan QKG, Thiffault I, Pastinen T, Sheikh K, Biliciler S, Mei D, Melani F, Shashi V, Yaron Y, Steele M, Wakeling E, Østergaard E, Nazaryan-Petersen L, Millan F, Santiago-Sim T, Thevenon J, Bruel AL, Thauvin-Robinet C, Popp D, Platzer K, Gawlinski P, Wiszniewski W, Marafi D, Pehlivan D, Posey JE, Gibbs RA, Gailus-Durner V, Guerrini R, Fuchs H, Hrabě de Angelis M, Hölter SM, Cheung HH, Gu S, and Lupski JR
Subjects: Animals, Humans, Mice, Cell Line, DEAD-box RNA Helicases genetics, Dichlorodiphenyl Dichloroethylene, DNA Helicases, Mammals, Neoplasm Proteins genetics, Charcot-Marie-Tooth Disease genetics, Neurodevelopmental Disorders
Abstract: DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9 -/- mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis., Competing Interests: Declaration of interests J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at the Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. F.M. and T.S.-S. are employees of GeneDx., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)
Published: 2023
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45. Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis.

Author: Tran Mau-Them F, Overs A, Bruel AL, Duquet R, Thareau M, Denommé-Pichon AS, Vitobello A, Sorlin A, Safraou H, Nambot S, Delanne J, Moutton S, Racine C, Engel C, De Giraud d'Agay M, Lehalle D, Goldenberg A, Willems M, Coubes C, Genevieve D, Verloes A, Capri Y, Perrin L, Jacquemont ML, Lambert L, Lacaze E, Thevenon J, Hana N, Van-Gils J, Dubucs C, Bizaoui V, Gerard-Blanluet M, Lespinasse J, Mercier S, Guerrot AM, Maystadt I, Tisserant E, Faivre L, Philippe C, Duffourd Y, and Thauvin-Robinet C
Abstract: Introduction: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Retrospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. Patients and methods: We applied a reanalysis strategy based on intensive prospective bibliographic monitoring along with direct application of the GREP command-line tool (to "globally search for a regular expression and print matching lines") in a large ES database. For 18 months, we submitted the same five keywords of interest [( intellectual disability , ( neuro ) developmental delay , and ( neuro ) developmental disorder )] to PubMed on a daily basis to identify recently published novel disease-gene associations or new phenotypes in genes already implicated in human pathology. We used the Linux GREP tool and an in-house script to collect all variants of these genes from our 5,459 exome database. Results: After GREP queries and variant filtration, we identified 128 genes of interest and collected 56 candidate variants from 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, GREP queries for only 128 genes over a period of 18 months permitted a causal diagnosis to be established in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP query strategy is efficient and less tedious than complete periodic reanalysis. It is an interesting reanalysis strategy to improve diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tran Mau-Them, Overs, Bruel, Duquet, Thareau, Denommé-Pichon, Vitobello, Sorlin, Safraou, Nambot, Delanne, Moutton, Racine, Engel, De Giraud d’Agay, Lehalle, Goldenberg, Willems, Coubes, Genevieve, Verloes, Capri, Perrin, Jacquemont, Lambert, Lacaze, Thevenon, Hana, Van-Gils, Dubucs, Bizaoui, Gerard-Blanluet, Lespinasse, Mercier, Guerrot, Maystadt, Tisserant, Faivre, Philippe, Duffourd and Thauvin-Robinet.)
Published: 2023
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46. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing.

Author: Denommé-Pichon AS, Matalonga L, de Boer E, Jackson A, Benetti E, Banka S, Bruel AL, Ciolfi A, Clayton-Smith J, Dallapiccola B, Duffourd Y, Ellwanger K, Fallerini C, Gilissen C, Graessner H, Haack TB, Havlovicova M, Hoischen A, Jean-Marçais N, Kleefstra T, López-Martín E, Macek M, Mencarelli MA, Moutton S, Pfundt R, Pizzi S, Posada M, Radio FC, Renieri A, Rooryck C, Ryba L, Safraou H, Schwarz M, Tartaglia M, Thauvin-Robinet C, Thevenon J, Tran Mau-Them F, Trimouille A, Votypka P, de Vries BBA, Willemsen MH, Zurek B, Verloes A, Philippe C, Vitobello A, Vissers LELM, and Faivre L
Subjects: Humans, Exome Sequencing, Alleles, Genotype, Intellectual Disability diagnosis, Intellectual Disability genetics
Abstract: Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned., Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted., Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency)., Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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47. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders.

Author: Colin E, Duffourd Y, Chevarin M, Tisserant E, Verdez S, Paccaud J, Bruel AL, Tran Mau-Them F, Denommé-Pichon AS, Thevenon J, Safraou H, Besnard T, Goldenberg A, Cogné B, Isidor B, Delanne J, Sorlin A, Moutton S, Fradin M, Dubourg C, Gorce M, Bonneau D, El Chehadeh S, Debray FG, Doco-Fenzy M, Uguen K, Chatron N, Aral B, Marle N, Kuentz P, Boland A, Olaso R, Deleuze JF, Sanlaville D, Callier P, Philippe C, Thauvin-Robinet C, Faivre L, and Vitobello A
Abstract: Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches. Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%-9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%-6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis. Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization. Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Colin, Duffourd, Chevarin, Tisserant, Verdez, Paccaud, Bruel, Tran Mau-Them, Denommé-Pichon, Thevenon, Safraou, Besnard, Goldenberg, Cogné, Isidor, Delanne, Sorlin, Moutton, Fradin, Dubourg, Gorce, Bonneau, El Chehadeh, Debray, Doco-Fenzy, Uguen, Chatron, Aral, Marle, Kuentz, Boland, Olaso, Deleuze, Sanlaville, Callier, Philippe, Thauvin-Robinet, Faivre and Vitobello.)
Published: 2023
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48. Exome sequencing as a first-tier test for copy number variant detection: retrospective evaluation and prospective screening in 2418 cases.

Author: Testard Q, Vanhoye X, Yauy K, Naud ME, Vieville G, Rousseau F, Dauriat B, Marquet V, Bourthoumieu S, Geneviève D, Gatinois V, Wells C, Willems M, Coubes C, Pinson L, Dard R, Tessier A, Hervé B, Vialard F, Harzallah I, Touraine R, Cogné B, Deb W, Besnard T, Pichon O, Laudier B, Mesnard L, Doreille A, Busa T, Missirian C, Satre V, Coutton C, Celse T, Harbuz R, Raymond L, Taly JF, and Thevenon J
Subjects: Humans, Retrospective Studies, High-Throughput Nucleotide Sequencing methods, Prospective Studies, DNA Copy Number Variations genetics, Exome genetics
Abstract: Background: Despite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%-20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES., Methods: This study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed., Results: On the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure., Conclusion: Combining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered., Competing Interests: Competing interests: QT, XV, LR and J-FT are employed by Eurofins Biomnis, a private medical biology laboratory. KY is employed by Seqone Genomics a private bioinformatics software provider., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2022
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49. Same performance of exome sequencing before and after fetal autopsy for congenital abnormalities: toward a paradigm shift in prenatal diagnosis?

Author: Bourgon N, Garde A, Bruel AL, Lefebvre M, Mau-Them FT, Moutton S, Sorlin A, Nambot S, Delanne J, Chevarin M, Pöe C, Thevenon J, Lehalle D, Jean-Marçais N, Kuentz P, Lambert L, El Chehadeh S, Schaefer E, Willems M, Laffargue F, Francannet C, Fradin M, Gaillard D, Blesson S, Goldenberg A, Capri Y, Sagot P, Rousseau T, Simon E, Binquet C, Ascencio ML, Duffourd Y, Philippe C, Faivre L, Vitobello A, and Thauvin-Robinet C
Subjects: Autopsy, Exome genetics, Female, Fetus abnormalities, Humans, Pregnancy, Prenatal Diagnosis, Ultrasonography, Prenatal, Exome Sequencing, Abnormalities, Multiple genetics, Congenital Abnormalities diagnosis, Congenital Abnormalities genetics, Congenital Abnormalities pathology
Abstract: Prenatal exome sequencing could be complex because of limited phenotypical data compared to postnatal/portmortem phenotype in fetuses affected by multiple congenital abnormalities (MCA). Here, we investigated limits of prenatal phenotype for ES interpretation thanks to a blindly reanalysis of postmortem ES data using prenatal data only in fetuses affected by MCA and harboring a (likely)pathogenic variant or a variant of unknown significance (VUS). Prenatal ES identified all causative variant previously reported by postmortem ES (22/24 (92%) and 2/24 (8%) using solo-ES and trio-ES respectively). Prenatal ES identified 5 VUS (in four fetuses). Two of them have been previously reported by postmortem ES. Prenatal ES were negative for four fetuses for which a VUS were diagnosed after autopsy. Our study suggests that prenatal phenotype is not a limitation for implementing pES in the prenatal assessment of unsolved MCA to personalize fetal medicine and could influence indication of postmortem examination., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)
Published: 2022
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50. Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study.

Author: Jouret G, Heide S, Sorlin A, Faivre L, Chantot-Bastaraud S, Beneteau C, Denis-Musquer M, Turnpenny PD, Coutton C, Vieville G, Thevenon J, Larson A, Petit F, Boudry E, Smol T, Delobel B, Duban-Bedu B, Fallerini C, Mari F, Lo Rizzo C, Renieri A, Caberg JH, Denommé-Pichon AS, Tran Mau-Them F, Maystadt I, Courtin T, Keren B, Mouthon L, Charles P, Cuinat S, Isidor B, Theis P, Müller C, Kulisic M, Türkmen S, Stieber D, Bourgeois D, Scalais E, and Klink B
Subjects: Cell Cycle Proteins genetics, Child, Female, Genomics, Humans, Mutation, Phenotype, Pregnancy, Transcription Factors genetics, De Lange Syndrome diagnosis, De Lange Syndrome genetics, De Lange Syndrome pathology, Nuclear Proteins genetics
Abstract: BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Published: 2022
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