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1. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool

Author

Frédéric Tran Mau-Them, Julian Delanne, Anne-Sophie Denommé-Pichon, Hana Safraou, Ange-Line Bruel, Antonio Vitobello, Aurore Garde, Sophie Nambot, Nicolas Bourgon, Caroline Racine, Arthur Sorlin, Sébastien Moutton, Nathalie Marle, Thierry Rousseau, Paul Sagot, Emmanuel Simon, Catherine Vincent-Delorme, Odile Boute, Cindy Colson, Florence Petit, Marine Legendre, Sophie Naudion, Caroline Rooryck, Clément Prouteau, Estelle Colin, Agnès Guichet, Alban Ziegler, Dominique Bonneau, Godelieve Morel, Mélanie Fradin, Alinoé Lavillaureix, Chloé Quelin, Laurent Pasquier, Sylvie Odent, Gabriella Vera, Alice Goldenberg, Anne-Marie Guerrot, Anne-Claire Brehin, Audrey Putoux, Jocelyne Attia, Carine Abel, Patricia Blanchet, Constance F. Wells, Caroline Deiller, Mathilde Nizon, Sandra Mercier, Marie Vincent, Bertrand Isidor, Jeanne Amiel, Rodolphe Dard, Manon Godin, Nicolas Gruchy, Médéric Jeanne, Elise Schaeffer, Pierre-Yves Maillard, Frédérique Payet, Marie-Line Jacquemont, Christine Francannet, Sabine Sigaudy, Marine Bergot, Emilie Tisserant, Marie-Laure Ascencio, Christine Binquet, Yannis Duffourd, Christophe Philippe, Laurence Faivre, and Christel Thauvin-Robinet

Subjects
exome sequencing (ES), chromosomal microarray, prenatal, fetal, diagnostic yield, Genetics, QH426-470
Abstract

Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

Published
2023
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2. Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

Author

Aurélien Trimouille, Florent Marguet, Fanny Sauvestre, Eulalie Lasseaux, Fanny Pelluard, Marie-Laure Martin-Négrier, Claudio Plaisant, Caroline Rooryck, Didier Lacombe, Benoît Arveiler, Odile Boespflug-Tanguy, Sophie Naudion, and Annie Laquerrière

Subjects
Vanishing white matter disease, Foetal neuropathology, Whole exome sequencing, Diagnosis, Pathophysiology, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

Published
2020
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4. First evidence of <scp> SOX2 </scp> mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

Author

Bertrand Chesneau, Marion Aubert‐Mucca, Félix Fremont, Jacmine Pechmeja, Vincent Soler, Bertrand Isidor, Mathilde Nizon, Hélène Dollfus, Josseline Kaplan, Lucas Fares‐Taie, Jean‐Michel Rozet, Tiffany Busa, Didier Lacombe, Sophie Naudion, Jeanne Amiel, Marlène Rio, Tania Attie‐Bitach, Cécile Lesage, Dominique Thouvenin, Sylvie Odent, Godelieve Morel, Catherine Vincent‐Delorme, Odile Boute, Clémence Vanlerberghe, Anne Dieux, Simon Boussion, Laurence Faivre, Lucile Pinson, Fanny Laffargue, Gwenaël Le Guyader, Guylène Le Meur, Fabienne Prieur, Victor Lambert, Beatrice Laudier, Edouard Cottereau, Carmen Ayuso, Marta Corton‐Pérez, Laurence Bouneau, Cédric Le Caignec, Véronique Gaston, Claire Jeanton‐Scaramouche, Delphine Dupin‐Deguine, Patrick Calvas, Nicolas Chassaing, Julie Plaisancié, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Jeunes Aveugles [Toulouse] (IJA), Clinique rive gauche, 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 de référence Maladies Rares CLAD-Ouest [Rennes], CHU Lille, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional d'Orléans (CHRO), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid (UAM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), French National Research AgencyFrench National Research Agency (ANR) [ANR-10-COHO-0003], and ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010)

Subjects
Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA Copy Number Variations, SOXB1 Transcription Factors, Peters' anomaly, [SDV]Life Sciences [q-bio], CNV, SOX2, eye diseases, PAX6, Corneal Opacity, microphthalmia, Anterior Eye Segment, Mutation, B3GLCT, Genetics, Humans, anterior segment dysgenesis, FOXE3, Eye Abnormalities, PITX3, Genetics (clinical)
Abstract

International audience; Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

Published
2022

5. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

6. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author

Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J. Louie, Michael J. Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley McConkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R. Roeder, Tadahiro Mitani, Jennifer E. Posey, Daniel Calame, Hagith Yonath, Jill A. Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R. Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello, Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yanni, Leblanc, Pontu, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M, Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J, Lyons, Michael J, Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, Mcconkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R, Mitani, Tadahiro, Posey, Jennifer E, Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A, Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R, Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio

Subjects
SRSF1, splicing, epigenetic signature, Medicine and Health Sciences, Genetics, Drosophila, neurodevelopmental disorder, Genetics (clinical), haploinsufficiency
Abstract

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

Published
2023

7. ARF1-related disorder: phenotypic and molecular spectrum

Author

Jean-Madeleine de Sainte Agathe, Ben Pode-Shakked, Sophie Naudion, Vincent Michaud, Benoit Arveiler, Patricia Fergelot, Jean Delmas, Boris Keren, Céline Poirsier, Fowzan S Alkuraya, Brahim Tabarki, Eric Bend, Kellie Davis, Martina Bebin, Michelle L Thompson, Emily M Bryant, Matias Wagner, Iris Hannibal, Jerica Lenberg, Martin Krenn, Kristen M Wigby, Jennifer R Friedman, Maria Iascone, Anna Cereda, Térence Miao, Eric LeGuern, Emanuela Argilli, Elliott Sherr, Oana Caluseriu, Timothy Tidwell, Pinar Bayrak-Toydemir, Caroline Hagedorn, Melanie Brugger, Katharina Vill, Francois-Dominique Morneau-Jacob, Wendy Chung, Kathryn N Weaver, Joshua W Owens, Ammar Husami, Bimal P Chaudhari, Brandon S Stone, Katie Burns, Rachel Li, Iris M de Lange, Margaux Biehler, Emmanuelle Ginglinger, Bénédicte Gérard, Rolf W Stottmann, and Aurélien Trimouille

Subjects
Genetics, Developmental defects, epilepsy, human genetics, sequence analysis, DNA, Genetics (clinical), ddc
Abstract

PurposeARF1was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum ofARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) withARF1variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) inARF1were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role ofARF1in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Published
2022

8. Atypical late diagnosis of Noonan syndrome revealed by bleedings due to platelet dysfunction

Author

Sabine-Marie Castet, Mathieu Fiore, Marie-Christine Alessi, Sophie Naudion, Jean-Claude Bordet, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Pediatrics, medicine.medical_specialty, Delayed Diagnosis, Platelet dysfunction, MEDLINE, Hemorrhage, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hematology, business.industry, Noonan Syndrome, medicine.disease, 3. Good health, Late diagnosis, Mutation, Noonan syndrome, Cardiology and Cardiovascular Medicine, business, Recherches cliniques, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2021

9. Lessons learned from 40 novel PIGA patients and a review of the literature

Author

Martin R. Larsen, Shiva Ganesan, Tobias Brünger, Nicolas Chassaing, Caroline Nava, Renzo Guerrini, Kim L. McBride, Anneke Kievit, Elena Parrini, Dennis Lal, Lisbeth Tranebjærg, Christel Depienne, Aleksandra Jezela-Stanek, Matthew Pastore, Carolina Fischinger Moura de Souza, Berten Ceulemans, Hannah Moore, Peter Krawitz, Gaetan Lesca, Ingo Helbig, Valerie Layet, Friedrich Bosch, Alexandra Afenjar, Rikke S. Møller, Carlos Ferreira, Sophie Naudion, Milda Endziniene, Alexej Knaus, Lilian Bomme Ousager, Marie-Christine Nougues, Caroline Karsenty, Johanne Kragh Hansen, Allan Bayat, Elena Gardella, Anne-Marie Guerrot, Marije Meuwissen, Tahsin Stefan Barakat, Mads Thomassen, Patrick Calvas, F Kooy, Jurgen H Schelhaas, Svetlana Gataullina, Lynne A. Wolfe, Bert Callewaert, Ashley Thomas, Steven A. Skinner, Lars Hansen, Manuela Pendziwiat, Cécile Freihuber, Cyril Mignot, Krzysztoł Szczałuba, Marjon van Slegtenhorst, Martino Montomoli, Christian Korff, and Clinical Genetics

Subjects
Adult, Male, 0301 basic medicine, Fryns syndrome phenotype, bioinformatical comparison, Medizin, Limb Deformities, Congenital, Cardiomyopathy, genotype-phenotype correlation, Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Humans, Clinical significance, mild developmental delay, Amino Acid Sequence, Global developmental delay, Child, Hernia, Diaphragmatic, Genetics, Infant, Newborn, Facies, Genetic Variation, Membrane Proteins, Electroencephalography, PIGA, medicine.disease, Magnetic Resonance Imaging, Phenotype, Hypotonia, 030104 developmental biology, Neurology, Cohort, Neurology (clinical), Human medicine, medicine.symptom, Congenital disorder of glycosylation, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.

Published
2020

10. De novo variants in ATP2B1 lead to neurodevelopmental delay

Author

Meer Jacob Rahimi, Nicole Urban, Meret Wegler, Heinrich Sticht, Michael Schaefer, Bernt Popp, Frank Gaunitz, Manuela Morleo, Vincenzo Nigro, Silvia Maitz, Grazia M.S. Mancini, Claudia Ruivenkamp, Eun-Kyung Suk, Tobias Bartolomaeus, Andreas Merkenschlager, Daniel Koboldt, Dennis Bartholomew, Alexander P.A. Stegmann, Margje Sinnema, Irma Duynisveld, Ramona Salvarinova, Simone Race, Bert B.A. de Vries, Aurélien Trimouille, Sophie Naudion, Daphna Marom, Uri Hamiel, Noa Henig, Florence Demurger, Nils Rahner, Enrika Bartels, J. Austin Hamm, Abbey M. Putnam, Richard Person, Rami Abou Jamra, Henry Oppermann, Rahimi, Meer Jacob, Urban, Nicole, Wegler, Meret, Sticht, Heinrich, Schaefer, Michael, Popp, Bernt, Gaunitz, Frank, Morleo, Manuela, Nigro, Vincenzo, Maitz, Silvia, Mancini, Grazia M S, Ruivenkamp, Claudia, Suk, Eun-Kyung, Bartolomaeus, Tobia, Merkenschlager, Andrea, Koboldt, Daniel, Bartholomew, Denni, Stegmann, Alexander P A, Sinnema, Margje, Duynisveld, Irma, Salvarinova, Ramona, Race, Simone, de Vries, Bert B A, Trimouille, Aurélien, Naudion, Sophie, Marom, Daphna, Hamiel, Uri, Henig, Noa, Demurger, Florence, Rahner, Nil, Bartels, Enrika, Hamm, J Austin, Putnam, Abbey M, Person, Richard, Abou Jamra, Rami, Oppermann, Henry, Clinical Genetics, MUMC+: DA KG Lab Specialisten (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output

Subjects
EXPRESSION, HOMEOSTASIS, de novo, seizure, HOUSEKEEPING FUNCTION, calcium homeostasi, Mutation, Missense, PLASMA-MEMBRANE CA2+-ATPASE, ISOFORMS, ATP2B1, Nervous System Malformations, development delay, abnormal behavior, Plasma Membrane Calcium-Transporting ATPases, CA2+, Report, BINDING, Genetics, Humans, MUTATION, Genetics (clinical), neurodevelopmental disorder, HEK293 Cells, Phenotype, Neurodevelopmental Disorders, intellectual disability
Abstract

Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder.

Published
2022

11. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD)

Author

Nadine Hanna, Tiffany Busa, Mélodie Aubart, Bruno Leheup, Laurence Faivre, Maud Langeois, Laurent Gouya, Jacques Ropers, Patrice Bouvagnet, Sophie Dupuis-Girod, Sophie Naudion, Louise Benarroch, Didier Lacombe, Olivier Milleron, Sylvie Odent, Maria Tchitchinadze, Guillaume Jondeau, Catherine Boileau, Pauline Arnaud, Yves Dulac, Thomas Edouard, Laurence Bal, Département de Génétique (Hôpital Bichat), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées (AP HP, hôpital Bichat), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Vasculaire (SCV-AP-MM Marseille), Hôpital Nord AP‐MM Marseille, France (AP‐MM Marseille), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU de Bordeaux Pellegrin [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and CARBILLET, Véronique

Subjects
Male, Proband, class 4 and 5 variants, Fibrillin-1, SMAD3 gene, MESH: Fibrillin-1 / genetics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Pathology, Molecular, MESH: Aneurysm, Dissecting / genetics, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), MESH: Aged, Aortic dissection, Genetics, FBN1 gene, MESH: Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Middle Aged, Predictive value, Pedigree, Codon, Nonsense, NGS, MESH: Aortic Aneurysm, Thoracic / genetics, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Premature Termination Codon, Adult, Adolescent, Autosomal dominant transmission, Young Adult, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Smad3 Protein, MESH: Codon, Nonsense / genetics, Gene, Aged, MESH: Adolescent, Genetic diversity, Aortic Aneurysm, Thoracic, business.industry, Genetic heterogeneity, MESH: Aortic Aneurysm, Thoracic / diagnosis, MESH: Aneurysm, Dissecting / diagnosis, MESH: Adult, MESH: Genetic Testing / methods, medicine.disease, thoracic aortic aneurysms and dissections, Aortic Dissection, Mutation, business, MESH: Aneurysm, Dissecting / physiopathology, MESH: Female
Abstract

International audience; Purpose : Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. Methods : Two hundred twenty-six consecutive nshTAAD probands, either young (

Published
2019

12. Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Author

Sophie Hambleton, Perrine Pennamen, John R. James, Meghan Acres, Wolfram Haller, Anas M. Alazami, Yasuhiro Yamazaki, James Thaventhiran, Jan Sinclair, Yu Zhang, Rainer Doffinger, Helen F. Matthews, David MacDonald, Zinan Zhang, Sophie Naudion, Kenneth G. C. Smith, Fanny Pelluard, Huda Alajlan, Yorgo Modis, Karin R. Engelhardt, Carlos P. Mata, Claire Bowen, Florian Gothe, Caroline Rooryck, Luigi D. Notarangelo, Hamoud Al-Mousa, Michael J. Lenardo, Zhang, Zinan [0000-0003-3831-2272], Mata, Carlos P [0000-0003-3381-7431], Modis, Yorgo [0000-0002-6084-0429], Haller, Wolfram [0000-0002-0518-7383], Sinclair, Jan [0000-0002-1188-0096], Pelluard, Fanny [0000-0003-1874-2742], Notarangelo, Luigi D [0000-0002-8335-0262], Thaventhiran, James E [0000-0001-8616-074X], Hambleton, Sophie [0000-0001-7954-3267], Smith, Kenneth GC [0000-0003-3829-4326], Lenardo, Michael J [0000-0003-1584-468X], and Apollo - University of Cambridge Repository

Subjects
STAT3 Transcription Factor, Interleukin 2, Genotype, T-Lymphocytes, Immunology, Mutation, Missense, Autoimmunity, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Aldesleukin, Immunity, Immune Tolerance, STAT5 Transcription Factor, medicine, Humans, Immunology and Allergy, Phosphorylation, Receptor, Alleles, Research Articles, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, Lentivirus, Immunologic Deficiency Syndromes, Peripheral tolerance, biochemical phenomena, metabolism, and nutrition, Immune dysregulation, 3. Good health, Interleukin-2 Receptor beta Subunit, Killer Cells, Natural, HEK293 Cells, Phenotype, IL2RB, business, Signal Transduction, 030215 immunology, medicine.drug
Abstract

Zhang et al. identify human IL-2Rβ deficiency as a cause of severe immune dysregulation. The hypomorphic gene mutations reveal variable IL-2Rβ expression and function between different lymphocyte subsets as a means of selectively modulating immune responses., Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2–based therapeutics for immunological diseases and cancer.

Published
2019

13. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author

Julien Thevenon, Sophie Blesson, Sylvie Manouvrier Hanu, Chloé Quélin, Florence Fellmann, Nicolas Chassaing, Fabienne Giuliano, Laetitia Lambert, Caroline Rooryck-Thambo, Pierre-Simon Jouk, Sylvie Di Filippo, Alexandre Vasiljevic, Christine Francannet, Daphné Lehalle, Audrey Putoux, Anna‐Gaëlle Giguet‐Valard, Sophie Naudion, Salima El Chehadeh, Estelle Colin, Viorica Ciorna‐Monferrato, Bruno Reversade, Lionel Van Maldergem, Fanny Morice-Picard, Renaud Touraine, Sébastien Moutton, Jocelyne Attia, Laurent Pasquier, A. Vigouroux-Castera, Catherine Yardin, Tania Attié-Bitach, Carine Abel, Hui Liu, Sylvie Odent, Christelle Cabrol, Florence Petit, Philippe Khau Van Kien, Thomas Simonet, Catherine Vincent-Delorme, Jean Chiesa, Juliette Piard, Anne Bazin, Mélanie Fradin, Bertrand Isidor, Loubna El Zein, Patrice Bouvagnet, Marie-Pierre Brechard, Emmanuelle Szenker-Ravi, Sophie Scheidecker, Claire Beneteau, and ACS - Heart failure & arrhythmias

Subjects
Heart Defects, Congenital, Male, midline anomaly, Heterozygote, medicine.medical_specialty, Genetic counseling, Consanguinity, Heterotaxy Syndrome, Biology, DNA sequencing, 03 medical and health sciences, consanguinity, Genetics, medicine, Humans, Family, Family history, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, Obstetrics, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, heterotaxy, congenital heart defects, Cardiac malformations, Pedigree, fetus, Parental consanguinity, Cytogenetic Analysis, Mutation, Female, next-generation sequencing, Heterotaxy
Abstract

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.

Published
2020

14. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Michael C. Kruer, Hanka Venselaar, Arjan P.M. de Brouwer, Eulalie Lasseaux, Rolph Pfundt, Emilia K. Bijlsma, Marieke F. van Dooren, Amélie Piton, Christian Gilissen, Maria J. Nabais Sá, Sophie Naudion, Renzo Guerrini, Bert B.A. de Vries, Didier Lacombe, André Reis, Michèl A.A.P. Willemsen, Laurens Wiel, Elisabeth Gabau, Annalisa Vetro, Regina Trollmann, Anna Ruiz, Catherine Vincent-Delorme, David A. Koolen, Aurélien Trimouille, Christiane Zweier, Monica S Cooper, David J. Amor, Tahsin Stefan Barakat, Somayeh Bakhtiari, Marjon van Slegtenhorst, Clinical Genetics, Radboud University Medical Center [Nijmegen], Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Radboud Institute for Molecular Life Sciences (RIMLS), CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jeanne de Flandre [Lille], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Universitat Autònoma de Barcelona (UAB), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Arizona, Murdoch Children's Research Institute (MCRI), University of Melbourne, Royal Children's Hospital Melbourne, Leiden University Medical Center (LUMC), and Erasmus University Medical Center [Rotterdam] (Erasmus MC)

Subjects
Microcephaly, media_common.quotation_subject, Population, Nonsense, Biology, Corpus Callosum, Frameshift mutation, CLTC, medicine, Humans, Missense mutation, education, Genetics (clinical), media_common, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, education.field_of_study, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, neurodevelopmental disorder, Phenotype, Biological Variation, Population, intellectual disability, Allelic heterogeneity, Haploinsufficiency, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 218155.pdf (Publisher’s version ) (Closed access) PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Published
2020

15. Author response for 'Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature'

Author

Laurence Faivre, Thibaud Jouan, Benjamin Cogné, Cornelia Kraus, V. Carmignac, Francis Ramond, Christiane Zweier, Emilie Tisserant, Mathilde Nizon, André Reis, Valérie Benoit, Daphné Lehalle, Antonio Vitobello, Bruno Delobel, Renaud Touraine, Thomas Smol, Arthur Sorlin, Yannis Duffourd, Sophie Naudion, Christel Thauvin-Robinet, T Bienvenu, Julien Thevenon, Caroline Thuillier, Patrick Callier, Stéphanie Moortgat, Frédéric Tran Mau-Them, Jamal Ghoumid, Christophe Philippe, Cécile Zordan, Sophie Nambot, and Alain Verloes

Subjects
business.industry, Female Phenotype, Immunology, Medicine, Disease, business
Published
2020

16. Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

Author

Christiane Zweier, Jamal Ghoumid, Cornelia Kraus, Sophie Nambot, Laurence Faivre, Antonio Vitobello, Stéphanie Moortgat, Thierry Bienvenu, Christel Thauvin-Robinet, Virginie Carmignac, Benjamin Cogné, Frédéric Tran Mau-Them, Julien Thevenon, Patrick Callier, Alain Verloes, Christophe Philippe, Sophie Naudion, Renaud Touraine, André Reis, Arthur Sorlin, Caroline Thuillier, Bruno Delobel, Thibaud Jouan, Francis Ramond, Cécile Zordan, Daphné Lehalle, Valérie Benoit, Yannis Duffourd, Mathilde Nizon, Emilie Tisserant, and Thomas Smol

Subjects
0301 basic medicine, Proband, Adult, Male, Heterozygote, X-linked intellectual disability, Genetic counseling, Disease, 030105 genetics & heredity, Biology, Short stature, 03 medical and health sciences, Young Adult, Genes, X-Linked, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, 10. No inequality, Exome, Genetics (clinical), Histone Demethylases, Epilepsy, Genetic heterogeneity, Genetic Variation, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, Child, Preschool, Mental Retardation, X-Linked, Female, medicine.symptom
Abstract

X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.

Published
2020

17. Maternal transmission ratio distortion of GNAS loss‐of‐function mutations

Author

Arnaud Molin, Nicolas Gruchy, Sylvie Paulien, Hervé Mittre, Sophie Naudion, Justine Bacchetta, Nicolas Richard, Laurence Faivre, Marion Gérard, Elise Schaefer, Sylvie Odent, Sarah Snanoudj, Marie-Laure Kottler, Bénédicte Demeer, Nadia Coudray, Cindy Colson, Alice Goldenberg, Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Œstrogènes, reproduction, cancer (OeReCa), Service de Génétique Clinique [Hautepierre Strasbourg], Hôpital de Hautepierre [Strasbourg], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL], Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, 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 Médicale du CHU de Bordeaux, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, 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), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)

Subjects
0301 basic medicine, Male, TRANSMISSION RATIO DISTORTION, Offspring, Endocrinology, Diabetes and Metabolism, Parenteral transmission, Population, PSEUDOHYPOPARATHYROIDISM, 030209 endocrinology & metabolism, medicine.disease_cause, 03 medical and health sciences, GNAS, 0302 clinical medicine, Genotype, medicine, GNAS complex locus, Chromogranins, GTP-Binding Protein alpha Subunits, Gs, Humans, Orthopedics and Sports Medicine, Allele, education, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Genetics, Mutation, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, POH, MUTATIONS, PPHP, PHP1A, medicine.disease, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Pseudopseudohypoparathyroidism, Female, Maternal Inheritance
Abstract

International audience; Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding Gs α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The mother-specific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of Gs α in oocyte biology or embryogenesis, with implications for genetic counseling. © 2019 American Society for Bone and Mineral Research.

Published
2019

18. CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays

Author

Tania Attié-Bitach, Pierre-Simon Jouk, Frédéric Brioude, Judith Melki, Sophie Julia, Abdelaziz Sefiani, Sophie Naudion, Stephen Stamm, Jennifer Fabre-Teste, Christine Francannet, Sébastien Mur, Muriel Holder-Espinasse, Nicole Revencu, Tiffany Busa, Marine Legendre, Alain Kitzis, Stanislas Lyonnet, Jeanne Amiel, Frédéric Bilan, Patricia Blanchet, Yassamine Doubaj, Massimiliano Rossi, Brigitte Gilbert-Dussardier, Marie-Ange Delrue, Montserrat Rodríguez-Ballesteros, Véronique Abadie, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - SSS/IREC/SLUC - Pôle St.-Luc

Subjects
Male, 0301 basic medicine, Sequence analysis, In silico, Computational biology, Biology, Real-Time Polymerase Chain Reaction, Brief Communication, 03 medical and health sciences, CHARGE syndrome, 0302 clinical medicine, Genetics, medicine, Humans, Genetics(clinical), Child, Genetics (clinical), DNA Helicases, Genetic disorder, Computational Biology, Sequence Analysis, DNA, medicine.disease, DNA-Binding Proteins, RNA Splice Sites, 030104 developmental biology, Chd7 gene, Mutation, RNA splicing, CHARGE Syndrome, 030217 neurology & neurosurgery, Minigene
Abstract

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3’ splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

Published
2017

19. Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Author

Linda Akloul, Véronique David, Clarisse Baumann, Sylvie Odent, Laurent Pasquier, Christèle Dubourg, Houda Hamdi-Rozé, Daniel Amram, Charlotte Mouden, Pierre Sarda, Sophie Naudion, Amélie Poidvin, Marie Gonzales, Nicolas Chassaing, Valérie Dupé, Fabienne Prieur, Joelle Roume, Marie de Tayrac, Benmansour Abdelmajid, Annie Levy-Mozziconacci, Christine Coubes, Wilfrid Carré, Annick Toutain, Laurence Faivre-Olivier, Emmanuelle Ginglinger, and Sally-Ann Lynch

Subjects
musculoskeletal diseases, 0301 basic medicine, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Fibroblast growth factor receptor 1, Genetic counseling, Biology, Quantitative trait locus, Bioinformatics, ZIC2, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, FGF8, Holoprosencephaly, GLI2, medicine, Gene, Genetics (clinical)
Abstract

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.

Published
2016

20. Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Author

John R. James, Zinan Zhang, Yorgo Modis, Karin R. Engelhardt, Carlos P. Mata, James Thaventhiran, Meghan Acres, Kenneth G. C. Smith, Anas M. Alazami, Rainer Doffinger, Jan Sinclair, Helen F. Matthews, Perrine Pennamen, David MacDonald, Yu Zhang, Sophie Naudion, Florian Gothe, Hamoud Al-Mousa, Fanny Pelluard, Michael J. Lenardo, Wolfram Haller, Claire Bowen, Sophie Hambleton, Yasuhiro Yamazaki, Caroline Rooryck, and Luigi D. Notarangelo

Subjects
0303 health sciences, Mutation, business.industry, Hypergammaglobulinemia, Peripheral tolerance, medicine.disease, medicine.disease_cause, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Immunology, medicine, Cytotoxic T cell, Missense mutation, IL-2 receptor, business, 030304 developmental biology, 030215 immunology
Abstract

Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of α, β and γ chains. Genetic deficiency of the α or γ chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) β chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2Rβ gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rβ expression and cytotoxic function. IL-2Rβ loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rβ expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Published
2018
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21. Author response for 'Fetal phenotype of Rubinstein-Taybi syndrome caused by CREBBP mutations'

Author

Tania Attié-Bitach, Bénédicte Demeer, Didier Lacombe, Patricia Fergelot M.D., Sandra Whalen, Benoit Arveiler, Jérôme Toutain, Sophie Naudion, Julien Van-Gils, Marie Gonzales, Gwenaelle Lancelot, Bérénice Doray, Sophie Blesson, Laurence Taine, and Jelena Martinovic

Subjects
Genetics, Fetus, Rubinstein–Taybi syndrome, business.industry, medicine, medicine.disease, business, Phenotype
Published
2018

22. Fetal phenotype of Rubinstein-Taybi syndrome caused by CREBBP mutations

Author

Julien Van-Gils, Jérôme Toutain, Marie Gonzales, Laurence Taine, Sophie Blesson, Sophie Naudion, Benoit Arveiler, Tania Attié-Bitach, Jelena Martinovic, Didier Lacombe, Gwenaelle Lancelot, Bérénice Doray, Bénédicte Demeer, Sandra Whalen, and Patricia Fergelot

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Genotype, Genetic counseling, Gene Dosage, Prenatal diagnosis, Autopsy, 030105 genetics & heredity, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Cerebellar hypoplasia, Fetal Death, Genetics (clinical), Genetic Association Studies, Rubinstein-Taybi Syndrome, Fetus, Pregnancy, Rubinstein–Taybi syndrome, business.industry, medicine.disease, CREB-Binding Protein, Developmental disorder, 030104 developmental biology, Phenotype, Mutation, Female, business
Abstract

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

Published
2018

23. Première description neuropathologique de deux fœtus porteurs de variants pathogènes d’EIF2B5

Author

Florent Marguet, Caroline Rooryck-Thambo, Marie-Laure Martin-Negrier, Eulalie Lasseaux, Odile Boespflug-Tanguy, Aurélien Trimouille, Fanny Sauvestre, Fanny Pelluard, Sophie Naudion, Annie Laquerrière, and Benoit Arveiler

Subjects
Anatomy
Abstract

Les variants pathogenes bi-alleliques des genes de la famille EIF2B ont ete rapportes comme responsables de leucodystrophies identifiees sous le terme de syndrome CACH/VWM, pour childhood ataxia with central nervous system hypomyelination/vanishing white matter disease [1] . Le spectre phenotypique est etendu, allant de leucodystrophies congenitales a des formes adultes. A ce jour, seuls 5 cas ont ete decrits a posteriori comme ayant presente des signes antenataux [2] , [3] . Nous presentons ici la premiere description de deux fœtus porteurs de variants deleteres du gene EIF2B5. Ces deux fœtus sont issus de deux grossesses d’un couple non consanguin, sans antecedent familial. Les grossesses ont ete interrompues a 27 et 32 semaines d’amenorrhee pour un phenotype similaire avec retard de croissance intra-uterin severe, associe a des anomalies cerebrales. L’examen neuropathologique a confirme ces anomalies, avec dans les deux cas une hypoplasie du cervelet, associe dans le second a un defaut de maturation estime a 24 semaines d’amenorrhee, des heterotopies de cellules de Purkinje, et une hypomyelinisation severe. Une CGH-array a ete realisee, et retrouvee normale. Le sequencage d’exomes en quatuor chez les deux fœtus et leurs parents a permis de mettre en evidence deux variants heterozygotes composites du gene EIF2B5 portes par les deux fœtus : c.468C>G p.Ile156Met, et c.1165G>A p.Val389Met. Ces variants sont absents de la base de donnees de population generale GnomAD, le variant Ile156Met ayant deja ete rapporte chez un patient presentant un syndrome CACH [2] . Le variant p.Val389Met n’avait pas ete precedemment rapporte, mais est predit deletere par l’ensemble des logiciels de prediction utilises. La concordance des elements anatomopathologiques avec les donnees des exomes a donc permis d’etablir le diagnostic de formes antenatales de syndrome CACH/VWM pour cette famille. L’etude de ces formes fœtales detectees par exome, de maladies precedemment decrites dans leurs formes post-natales, peut permettre d’en eclairer les processus physiopathologiques.

Published
2019

24. Fetal phenotypes in otopalatodigital spectrum disorders

Author

Philippe Loget, Didier Lacombe, Marie-Pierre Cordier, Sébastien Moutton, Cyril Goizet, C. Abel, Cédric Hubert, Sophie Patrier, Julie Pilliod, G. Viot, Benoit Arveiler, Bettina Bessières, Alice Goldenberg, Julie Deforges, Isabelle Coupry, Caroline Rooryck, G. Sole, Anne-Lise Delezoide, Sophie Blesson, Patricia Fergelot, Elodie Guerineau, Alain Verloes, Judith Melki, F. Le Breton, S. Deves, Sophie Collardeau-Frachon, Sylvie Odent, and Sophie Naudion

Subjects
0301 basic medicine, Genetics, Mutation, Mutation rate, Omphalocele, Craniofacial abnormality, Genetic counseling, 030105 genetics & heredity, Biology, medicine.disease_cause, Bioinformatics, medicine.disease, 3. Good health, 03 medical and health sciences, Dysplasia, medicine, FLNA, Obstructive uropathy, Genetics (clinical)
Abstract

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

Published
2015

25. Marfan Sartan: a randomized, double-blind, placebo-controlled trial

Author

H. Plauchu, Francois Sassolas, F. Arnoult, G. Delorme, Florence Tubach, Sophie Naudion, Guillaume Jondeau, Jacques Ropers, Olivier Milleron, Sylvie Odent, Martine Barthelet, Delphine Detaint, Philippe Aegerter, Nicolas Pangaud, Catherine Boileau, Thomas Edouard, Sophie Dupuis-Girod, Gilbert Habib, Jean-Eric Wolf, David Attias, Laurence Faivre, Adeline Basquin, Patrick Collignon, Yves Dulac, Julie Thomas-Chabaneix, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'explorations fonctionnelles, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS), AFSSAPS, Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de santé publique, Hôpital Ambroise Paré [AP-HP], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Université Paris Diderot - Paris 7 (UPD7), CIC epidémiologie clinique/ essais cliniques, Hôpital Bichat - Claude Bernard, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, Hôtel Dieu, Service pédiatrie-cardiologie, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Cardiologie [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), 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 cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique Médicale, Centre Hospitalier Intercommunal, Toulon, 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), Centre de référence MARFAN, Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], AP-HP, Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Service de cardiologie et maladies vasculaires, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Dispositifs, diagnostics et thérapeutiques, and Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Marfan syndrome, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Adrenergic beta-Antagonists, Aortic Diseases, Placebo-controlled study, Blood Pressure, Placebo, Sudden death, Drug Administration Schedule, Losartan, Marfan Syndrome, Young Adult, Double-Blind Method, Heart Rate, medicine.artery, Internal medicine, Marfan, Humans, Medicine, Prospective Studies, Systole, Aorta, Aged, Sartan, business.industry, Middle Aged, medicine.disease, 3. Good health, Blood pressure, Echocardiography, Hypertension, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Angiotensin II Type 1 Receptor Blockers, Dilatation, Pathologic, medicine.drug
Abstract

AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when \textless50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age \textgreater10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients \textgreater10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients

Published
2015

26. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Author

Montserrat Rodríguez-Ballesteros, Laurence Faivre, Pierre-Simon Jouk, Christine Francannet, Damien Sanlaville, Sophie Naudion, Hélène Dollfus, Nicole Philip, Pierre Sarda, Marine Legendre, X. Piguel, Alice Masurel-Paulet, Marie-Ange Delrue, Frédéric Bilan, Aurélia Jacquette, Dominique Bonneau, Catherine Vincent-Delorme, Valérie Layet, Michèle Mathieu-Dramard, Delphine Héron, Sébastien Moutton, Alice Goldenberg, Sophie Julia, Sophie Blesson, Sylvie Odent, Philippe Parent, Chloé Quélin, Estelle Colin, Mélanie Fradin, Anne-Marie Guerrot, David Geneviève, Lucile Pinson, Renaud Touraine, Sabine Sigaudy, Stéphanie Ragot, Didier Lacombe, Massimiliano Rossi, Salima El Chehadeh, Tiffany Busa, Annick Toutain, Stanislas Lyonnet, Véronique Abadie, Bruno Leheup, Dominique Martin-Coignard, Tania Attié-Bitach, Brigitte Gilbert-Dussardier, Sandra Mercier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-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 [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), 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), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Endocrinologie [CHU Poitiers], Service Génétique Médicale [CHU Poitiers], French Ministry of Health ID-RCB: 2010-A00700-39, Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), 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 ), Institut de Médecine Aérospatiale du Service de Santé des Armées ( IMASSA ), Service de Santé des Armées, Université d'Angers ( UA ) -CHU Angers, Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Bretonneau-CHRU Tours, Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique médicale et cytogénétique [Le Mans], CH Le Mans, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CLAD Ouest, Centre Hospitalier Universitaire [Rennes], 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 des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, CHU - HÔTEL-DIEU Clermont-Ferrand, CHU Bordeaux [Bordeaux], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, 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 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Cardiologie, Pôle DUNE, CHU de Poitiers, Centre d' investigation clinique-plurithématique du CHU de Poitiers, Génétique Médicale, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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 National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, université de Bourgogne, GAD, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), 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), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
0301 basic medicine, Central Nervous System, Male, update, Choanal atresia, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Gastroenterology, spectrum, Cohort Studies, CHARGE syndrome, Genotype, Medicine, Child, Genetics (clinical), Coloboma, Genetic disorder, Cranial Nerves, Hypoplasia, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, Child, Preschool, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Anosmia, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, otorhinolaryngologic diseases, Humans, Abnormalities, Multiple, Genetic Testing, Alleles, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, association, DNA Helicases, Infant, medicine.disease, mutations, diagnostic-criteria, 030104 developmental biology, Amino Acid Substitution, Atresia, chd7 gene, proposal, CHARGE Syndrome, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract

International audience; CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.

Published
2017

27. Copy Number Variations Found in Patients with a Corpus Callosum Abnormality and Intellectual Disability

Author

Isabelle Marey, Anne Faudet, Sandra Chantot-Bastaraud, Caroline Rooryck, Annick Toutain, Damien Haye, Vincent des Portes, Corinne Mach, Laurence Olivier-Faivre, Thierry Billette de Villemeur, Sandra Whalen, Eric Fonteneau, Marie-Laure Moutard, Delphine Héron, Alice Masurel-Paulet, D Sanlaville, Sophie Naudion, Christel Depienne, Cyril Mignot, Cédric Le Caignec, Christel Thauvin-Robinet, Didier Lacombe, Caroline Nava, Dorothée Ville, Aurélia Jacquette, Boris Keren, Jean-Pierre Siffroi, Fabien Lesne, Solveig Heide, Elodie Lejeune, université de Bourgogne, LNC, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), Université de Lyon, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique et embryologie médicales [CHU Trousseau], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Candidate gene, Cell Cycle Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Corpus callosum, Bioinformatics, corpus callosum, chromosomal microarray, Chromosome Duplication, Intellectual disability, Gene duplication, Basic Helix-Loop-Helix Transcription Factors, Prospective Studies, Copy-number variation, Child, Genetics, TCF4, agenesis of corpus callosum, Child, Preschool, Female, Chromosomes, Human, Pair 3, Chromosome Deletion, SNP array, Chromosomes, Human, Pair 7, Chromosomes, Human, Pair 8, Adult, Adolescent, DNA Copy Number Variations, CNV, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, Intellectual Disability, mental disorders, medicine, Humans, SNP, Hedgehog Proteins, dysgenesis of corpus callosum, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, business.industry, Zinc Finger E-box-Binding Homeobox 1, Microarray Analysis, medicine.disease, 030104 developmental biology, Pediatrics, Perinatology and Child Health, business, Chromosomes, Human, Pair 19
Abstract

International audience; OBJECTIVE:To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays.RESULTS:In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes.CONCLUSIONS:Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.Copyright © 2017 Elsevier Inc. All rights reserved.

Published
2017

28. New candidate loci identified by array-CGH in a cohort of 100 children presenting with syndromic obesity

Author

Didier Lacombe, Isabelle Kieffer, Caroline Rooryck, Anja Knoll-Gellida, Laurence Bouneau, Fabienne Nacka, Béatrice Jouret, Sophie Julia, Georges Bourrouillou, Marie-Laure Vuillaume, Adeline Vigouroux, Guillaume Banneau, Gwenaelle Diene, Audrey Cartault, David Geneviève, Jérôme Toutain, Sophie Naudion, Maithé Tauber, Pierre Sarda, Julie Bouron, Benoit Arveiler, Pascal Barat, Patrick J. Babin, Laurence Faivre, Marie-Ange Delrue, Eric Bieth, and Dorothée Cailley

Subjects
Male, CNTNAP2, Candidate gene, DNA Copy Number Variations, Quantitative Trait Loci, Gene Expression, Chromosome Disorders, Biology, Bioinformatics, Gene duplication, Intellectual disability, Genetics, medicine, Humans, Obesity, Copy-number variation, Child, Genetic Association Studies, Genetics (clinical), Chromosome Aberrations, Comparative Genomic Hybridization, Infant, Genomics, Syndrome, medicine.disease, Phenotype, Child, Preschool, Cohort, Etiology, Female, Genome-Wide Association Study, Comparative genomic hybridization
Abstract

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

Published
2014

29. Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance

Author

Zinan Zhang, Florian Gothe, Perrine Pennamen, John James, David McDonald, Carlos Mata, Yorgo Modis, Anas Alazami, Megan Acres, Wolfram Haller, Claire Bowen, Rainer Doffinger, Jan Sinclair, Shannon Brothers, Yu Zhang, Helen Matthews, Sophie Naudion, Fanny Pelluard, Huda Alajlan, Yasuhiro Yamazaki, Luigi Notarangelo, James Thaventhiran, Karin Engelhardt, Hamoud Al-Mousa, Sophie Hambleton, Caroline Rooryck, Kenneth G.C. Smith, and Michael J Lenardo

Subjects
Immunology, Immunology and Allergy
Abstract

Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor. Genetic deficiency of the alpha or gamma chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) beta chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the human IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rbeta and were unable to respond normally to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rbeta expression and cytotoxic function. IL-2Rbeta loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rbeta expression between different lymphocyte subsets and during their maturation as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Published
2019

30. Expanding the clinical phenotype at the 3q13.31 locus with a new case of microdeletion and first characterization of the reciprocal duplication

Author

Didier Lacombe, Marie-Laure Vuillaume, Sophie Naudion, Benoit Arveiler, Jérôme Toutain, Marie-Ange Delrue, Patricia Fergelot, and Caroline Rooryck

Subjects
Male, Candidate gene, Adolescent, Cell Adhesion Molecules, Neuronal, Developmental Disabilities, Endocrinology, Diabetes and Metabolism, Gene Dosage, Nerve Tissue Proteins, Locus (genetics), Biology, GPI-Linked Proteins, Biochemistry, GAP-43 Protein, Endocrinology, Genes, Duplicate, Gene expression, Intellectual disability, Gene duplication, Genetics, medicine, Humans, Obesity, Molecular Biology, Gene, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, Receptors, Dopamine D3, Microdeletion syndrome, medicine.disease, Phenotype, Female, Chromosomes, Human, Pair 3, Chromosome Deletion, Gene Deletion, Transcription Factors
Abstract

Congenital deletions at the 3q13.31 locus have been recently described as a novel microdeletion syndrome characterized by developmental delay, postnatal overgrowth, hypoplastic male genitalia and characteristic facial features. A common critical region of overlapping of 580kb was delineated including two strong candidate genes for developmental delay: DRD3 and ZBTB20. In this report, we describe a new case of 3q13.31 microdeletion identified by array-CGH in a 16year-old girl sharing clinical features commonly observed in the 3q13.31 microdeletion syndrome. This girl had a microdeletion of 7.39Mb spanning the common critical region of overlapping. More interestingly, we report for the first time the existence of a microduplication reciprocal to the microdeletion syndrome. This familial 2.76Mb microduplication identified by array-CGH was carried by two brothers and their father. The phenotype shared by the brothers resembled the phenotype related to the 3q13.31 microdeletion syndrome including especially severe intellectual disability, developmental delay, behavioral abnormalities and obesity. This microduplication involves three strong candidate genes for the developmental delay ZBTB20, LSAMP and GAP43. Further molecular characterization showed that DRD3, another strong candidate gene for developmental delay, was not included in the duplicated region. However, a dosage alteration of this gene cannot be completely excluded as the duplication was inverted at proximity of this gene, as revealed by FISH analysis. Finally, we hypothesized that the phenotype shared by the two brothers could be related to a gene dosage imbalance even if gene expression could not be measured in relevant tissues such as brain or adipocytes.

Published
2013

31. Anatomie pathologique de l’insuffisance vasculaire utéroplacentaire

Author

Marion Poingt, Claire Castain, Sophie Naudion, Fanny Pelluard, Dominique Carles, Gwenaëlle André, and Fanny Sauvestre

Subjects
Pathology, medicine.medical_specialty, medicine.anatomical_structure, Fetal death, Growth retardation, business.industry, Placenta, medicine, Context (language use), Vascular insufficiency, business, Pathological, Pathology and Forensic Medicine
Abstract

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.

Published
2013

32. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome

Author

Gwenaëlle Collod-Béroud, Olivier Milleron, Sylvie Odent, Sophie Dupuis-Girod, Nadine Hanna, Guillaume Jondeau, Catherine Boileau, Mélodie Aubart, Bruno Leheup, Didier Lacombe, Sophie Naudion, Maud Langeois, Laurence Bal, Pauline Arnaud, Laurent Gouya, Myrtille Spentchian, Laurence Faivre, Thomas Edouard, Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées (AP HP, hôpital Bichat), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de Génétique Clinique Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Service de Génétique Médicale du CHU de Bordeaux, Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Chirurgie vasculaire (Hôpital de la Timone adultes), Hôpital de la Timone [CHU - APHM] (TIMONE), Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Pédiatrie - Cardiologie ( CHU de Toulouse), CHU Toulouse [Toulouse], and COLLOD-BEROUD, Gwenaëlle

Subjects
0301 basic medicine, Proband, Marfan syndrome, musculoskeletal diseases, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, Fibrillin-1, Mutation, Missense, Context (language use), macromolecular substances, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030105 genetics & heredity, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Compound heterozygosity, Homozygosity, Marfan Syndrome, 03 medical and health sciences, Genetic heterogeneity, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Molecular genetics, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Pathology, Molecular, Genetics (clinical), Alleles, FBN1 gene, Homozygote, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Connective tissue disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Female
Abstract

IF 5.451; International audience; Background Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation.Objectives Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases.Methods and results In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands.Conclusion Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.

Published
2016

33. International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium)

Author

Sophie Dupuis-Girod, Shaine A. Morris, Guillaume Jondeau, Myrtille Spentchian, Arturo Evangelista, Katherine Holman, Maud Langeois, Sophie Naudion, Catherine Boileau, Hiroto Morisaki, Leslie C. Adès, Reed E. Pyeritz, Ellen S. Regalado, Richmond W. Jeremy, Julie De Backer, Takayuki Morisaki, Alan C. Braverman, Scott A. LeMaire, Olivier Milleron, Cécile Zordan, Yskert von Kodolitsch, Sylvie Odent, Dianna M. Milewicz, Mélodie Aubart, Guisela Teixedo, Madhura Bakshi, Jacques Ropers, and Laura Muiño-Mosquera

Subjects
0301 basic medicine, Marfan syndrome, Male, Receptor, Transforming Growth Factor-beta Type I, Aorta, Thoracic, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Loeys–Dietz syndrome, Severity of Illness Index, 0302 clinical medicine, Japan, Pregnancy, Risk Factors, Prevalence, Medicine, Registries, Genetics (clinical), Aortic dissection, Natural history, Europe, Phenotype, Treatment Outcome, Cardiology, Female, Cardiology and Cardiovascular Medicine, Vascular Surgical Procedures, medicine.medical_specialty, Heterozygote, Pregnancy Complications, Cardiovascular, Aortic Diseases, Protein Serine-Threonine Kinases, Aortic disease, Article, 03 medical and health sciences, Aneurysm, Internal medicine, Genetics, Humans, In patient, Genetic Predisposition to Disease, Proportional Hazards Models, Retrospective Studies, business.industry, Australia, Receptor, Transforming Growth Factor-beta Type II, Aortic surgery, medicine.disease, United States, 030104 developmental biology, Mutation, business, Receptors, Transforming Growth Factor beta
Abstract

Background— The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. Methods and Results— The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2 . Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. Conclusions— Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.

Published
2016

34. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Author

Marie, Vincent, David, Geneviève, Agnès, Ostertag, Sandrine, Marlin, Didier, Lacombe, Dominique, Martin-Coignard, Christine, Coubes, Albert, David, Stanislas, Lyonnet, Catheline, Vilain, Anne, Dieux-Coeslier, Sylvie, Manouvrier, Bertrand, Isidor, Marie-Line, Jacquemont, Sophie, Julia, Valérie, Layet, Sophie, Naudion, Sylvie, Odent, Laurent, Pasquier, Sybille, Pelras, Nicole, Philip, Geneviève, Pierquin, Fabienne, Prieur, Nisrine, Aboussair, Tania, Attie-Bitach, Geneviève, Baujat, Patricia, Blanchet, Catherine, Blanchet, Hélène, Dollfus, Bérénice, Doray, Elise, Schaefer, Patrick, Edery, Fabienne, Giuliano, Alice, Goldenberg, Cyril, Goizet, Agnès, Guichet, Christian, Herlin, Laetitia, Lambert, Bruno, Leheup, Jelena, Martinovic, Sandra, Mercier, Cyril, Mignot, Marie-Laure, Moutard, Marie-José, Perez, Lucile, Pinson, Jacques, Puechberty, Marjolaine, Willems, Hanitra, Randrianaivo, Kateline, Szakszon, Kateline, Szaskon, Annick, Toutain, Alain, Verloes, Jacqueline, Vigneron, Elodie, Sanchez, Pierre, Sarda, Jean-Louis, Laplanche, Corinne, Collet, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, 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), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Génétique Humaine, Université de Liège-CHU Liège, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre [Strasbourg], 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), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale, Head of the Department of Medical Genetics, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), 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 ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [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 ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), 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 ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Bretonneau-CHRU Tours, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Lavoisier de Versailles ( ILV ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), 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 National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Adult, Male, 0301 basic medicine, Franceschetti syndrome, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Treacher Collins syndrome, Young Adult, 03 medical and health sciences, medicine, Humans, Base sequence, POLR1D, Amino Acid Sequence, Child, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Sequence Deletion, phenotype–genotype correlations, Base Sequence, [ SDV ] Life Sciences [q-bio], Nuclear Proteins, Large series, DNA-Directed RNA Polymerases, Mandibulofacial dysostosis, Middle Aged, Peptide Elongation Factors, Phosphoproteins, medicine.disease, Dermatology, 3. Good health, Surgery, TCOF1, 030104 developmental biology, Mutation, Microcephaly, Female, Mandibulofacial Dysostosis
Abstract

International audience; Purpose - Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. Methods - We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. Results - We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Conclusion - Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

Published
2016

35. SETD5 haploinsufficiency phenotypic refinement: Expanding the range of chromatin disorders

Author

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

Subjects
Genetics, Range (biology), Pediatrics, Perinatology and Child Health, Neurology (clinical), General Medicine, Biology, Haploinsufficiency, Phenotype, Chromatin
Published
2017

36. Aspect labyrinthique des vaisseaux villositaires dans les môles partielles. Intérêt pour le diagnostic anatomopathologique de môle partielle sur biopsie de villosités choriales

Author

Dominique Carles, Gwenaëlle André, Robert Saura, Sophie Naudion, and Fanny Pelluard

Subjects
Gynecology, medicine.medical_specialty, business.industry, medicine, business, Partial mole, Pathology and Forensic Medicine
Abstract

Resume Nous decrivons un cas d’aspect labyrinthique des vaisseaux villositaires observe sur une biopsie de villosites choriales. Ces images sont pathognomoniques d’une mole partielle et le caractere triploide de cette grossesse a ensuite ete confirme par un caryotype. Les aspects labyrinthiques des vaisseaux des villosites choriales ont deja ete decrits sur des produits d’avortement spontane ou d’interruption medicale de grossesse, mais ils n’ont jamais ete decrits sur des biopsies de villosites choriales. L’analyse histologique des biopsies de villosites choriales ne permet que rarement de porter un diagnostic d’aberration chromosomique, a l’exception des triploidies a type de mole partielle pour lesquelles les criteres microscopiques sont le plus souvent caracteristiques.

Published
2009

37. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum

Author

Pierre Sarda, Guilhem Solé, Fabienne Giuliano, Cyril Goizet, Marie-Ange Delrue, Eva-Lena Stattin, Patricia Fergelot, Nada Houcinat, Hubert Journel, Jacqueline Vigneron, Elisabeth Sarrazin, Benoit Arveiler, S. Deves, Laurence Faivre, Albert David, Clarisse Baumann, Martine Le Merrer, Caroline Abadie, Caroline Rooryck, Elodie Guerineau, Sophie Naudion, Marie-Laure Vuillaume, Nicolas Chassaing, Julie Bouron, Sébastien Moutton, Isabelle Coupry, David Geneviève, Marie-Pierre Cordier, Julie Deforges, Christine Francannet, Didier Lacombe, Danielle Leclair, André Mégarbané, Christophe Hubert, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Arabian Gulf University, 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), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de médecine physique et réadaptation [CHU Raymond-Poincaré], Hôpital Raymond Poincaré [AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Bretagne Atlantique [Vannes], Service de génétique médicale [Clermont-Ferrand], CHU Clermont-Ferrand, and AP-HP Hôpital Raymond Poincaré [Garches]

Subjects
0301 basic medicine, Proband, Male, MESH: Sequence Analysis, DNA, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Craniofacial Abnormalities, FLNA, Missense mutation, Genetics (clinical), Genetics, MESH: Osteochondrodysplasias / genetics, Mutation, MESH: Hand Deformities, Congenital / genetics, Exons, MESH: Amino Acid Substitution, Pedigree, Phenotype, MESH: Facies, Statistical genetics, Medical genetics, Female, MESH: Osteochondrodysplasias / diagnosis, MESH: Genetic Association Studies, Hand Deformities, Congenital, medicine.medical_specialty, MESH: Pedigree, MESH: Phenotype, Filamins, Biology, Osteochondrodysplasias, MESH: Craniofacial Abnormalities / diagnosis, 03 medical and health sciences, medicine, Humans, MESH: Filamins / genetics, Alleles, Genetic Association Studies, MESH: Hand Deformities, Congenital / diagnosis, MESH: Humans, MESH: Alleles, Facies, Sequence Analysis, DNA, medicine.disease, MESH: Craniofacial Abnormalities / genetics, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, Dysplasia, MESH: Mutation, MESH: Exons, MESH: Female
Abstract

International audience; Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.

Published
2015

38. Tamponnade sur thrombose de la veine interventriculaire antérieure compliquant un cathétérisme veineux central chez un nouveau-né

Author

Sophie Naudion, Béatrice Baudoin, Marine Legendre, Fanny Pelluard, Dominique Carles, Gwenaëlle André, and Christian Boucard

Subjects
medicine.medical_specialty, business.industry, Perforation (oil well), medicine.disease, Atrial wall, Thrombosis, Pathology and Forensic Medicine, Surgery, Lesion, Venous thrombosis, Catheter, medicine, Tamponade, medicine.symptom, Complication, business
Abstract

Tamponade is a rare but particularly serious complication of central venous catheters in the newborn. Tamponade can be due to the endocardic aggression caused by the continuous flow of a hyperosmotic solution or by a mechanical injury that can result in perforation of the atrial wall. The risk of tamponade is present whatever is the position of the tip of the catheter, although it has been shown that this risk is increased when this tip is in the right auricle. The originality of our observation is the discovery at the post-mortem examination of an anterior interventricular vein thrombosis, without any lesion of the atrial wall. In the event of the diagnosis of tamponade in living newborn, this etiology must be required because of its therapeutic implications.

Published
2012

39. [Placental pathology of uteroplacental vascular deficiency]

Author

Dominique, Carles, Fanny, Pelluard, Gwenaëlle, André, Sophie, Naudion, Marion, Poingt, Claire, Castain, and Fanny, Sauvestre

Subjects
Fibrin, Placenta Diseases, Cysts, Placenta, Uterus, Gestational Age, Organ Size, Fetal Hypoxia, Trophoblasts, Pregnancy Complications, Necrosis, Chorionic Villi Sampling, Infarction, Pregnancy, Humans, Female, Placental Circulation, Chorionic Villi, Fetal Death
Abstract

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.

Published
2012

40. [Cardiac tamponade with anterior interventricular vein thrombosis complicating central venous catheter insertion in a neonate]

Author

Dominique, Carles, Christian, Boucard, Béatrice, Baudoin, Fanny, Pelluard, Gwenaëlle, André, Sophie, Naudion, and Marine, Legendre

Subjects
Venous Thrombosis, Catheterization, Central Venous, Fatal Outcome, Heart Ventricles, Diseases in Twins, Infant, Newborn, Humans, Female, Cardiac Tamponade
Abstract

Tamponade is a rare but particularly serious complication of central venous catheters in the newborn. Tamponade can be due to the endocardic aggression caused by the continuous flow of a hyperosmotic solution or by a mechanical injury that can result in perforation of the atrial wall. The risk of tamponade is present whatever is the position of the tip of the catheter, although it has been shown that this risk is increased when this tip is in the right auricle. The originality of our observation is the discovery at the post-mortem examination of an anterior interventricular vein thrombosis, without any lesion of the atrial wall. In the event of the diagnosis of tamponade in living newborn, this etiology must be required because of its therapeutic implications.

Published
2010

41. [Maze-like vascular anomaly in partial mole. Interest for the pathological diagnosis of partial mole on chorionic villous sampling]

Author

Dominique, Carles, Fanny, Pelluard, Gwenaëlle, André, Sophie, Naudion, and Robert, Saura

Subjects
Adult, Chorionic Villi Sampling, Pregnancy, Uterine Neoplasms, Humans, Female, Hydatidiform Mole
Abstract

A case of maze-like angiomatoid anomaly in villi obtained by chorionic villous sampling (CVS) is described. This feature is pathognomonic of partial mole (triploid syndrome) and it was later confirmed by chromosomal analysis. Maze-like angiomatoid anomaly was previously described on specimen submitted after spontaneous or induced abortions, but it was never reported on CVS. This report emphasized that microscopic investigation of CVS cannot be conclusive for cytogenetic anomaly in almost all cases excepted for partial mole where diagnosis criteria are usually characteristic.

Published
2009

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