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1. MYH9‐related disease: Assessment of the pathogenicity of a new mutation

Author: Babuty Antoine, Pierre Boisseau, Nicolas Drillaud, Marion Eveillard, and Marc Fouassier
Subjects: genetic, immunofluorescence, macrothrombocytopenia, MYH9‐related disease, Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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2. Identification of von Willebrand factor D4 domain mutations in patients of Afro‐Caribbean descent: In vitro characterization

Author: Marie‐Daniéla Dubois, Ivan Peyron, Olivier‐Nicolas Pierre‐Louis, Serge Pierre‐Louis, Johalène Rabout, Pierre Boisseau, Annika deJong, Sophie Susen, Jenny Goudemand, Rémi Neviere, Pascal Fuseau, Olivier D. Christophe, Peter J. Lenting, Cécile V. Denis, and Caterina Casari
Subjects: binding assays, intracellular retention, recombinant proteins, von Willebrand disease, von Willebrand factor, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Abstract Background Von Willebrand disease was diagnosed in two Afro‐Caribbean patients and sequencing of the VWF gene (VWF) revealed the presence of multiple variants located throughout the gene, including variants located in the D4 domain of VWF: p.(Pro2145Thrfs*5) in one patient and p.(Cys2216Phefs*9) in the other patient. Interestingly, D4 variants have not been studied often. Objectives Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods Recombinant VWF (rVWF), mutant or wild‐type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild‐type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results Homozygous expression of the p.(Cys2216Phefs*9)‐rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild‐type‐rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)‐rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild‐type‐rVWF. Conclusions We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.
Published: 2022
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3. A Combination of Two Variants p. (Val510 =) and p. (Pro2145Thrfs * 5), Responsible for von Willebrand Disease Type 3 in a Caribbean Patient

Author: Marie Daniela Dubois, Serge Pierre-Louis, Johalène Rabout, Cécile V. Denis, Olivier Christophe, Sophie Susen, Jenny Goudemand, Pierre Boisseau, Rémi Neviere, and Olivier Pierre-Louis
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Published: 2020
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4. Differential diagnosis of neonatal alloimmune thrombocytopenia: Type 2B von Willebrand disease

Author: Mathilde Penel-Page, Sandrine Meunier, Mathilde Fretigny, Sandra Le Quellec, Pierre Boisseau, Christine Vinciguerra, Catherine Ternisien, and Lucia Rugeri
Subjects: neonatal alloimmune thrombocytopenia, neonatal thrombocytopenia, type 2b von willebrand disease, von willebrand factor, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: At birth, severe thrombocytopenia without context of infection should mainly suggest neonatal alloimmune thrombocytopenia (NAIT), especially in case of a platelet count below 20 GL−1. We report two cases of severe neonatal thrombocytopenia, first suspected as being NAIT. Both had a platelet count below 20 GL−1 with platelet clumps. The absence of alloantibodies and failure of platelet transfusion and intravenous immunoglobulins to improve the platelet count led to question the diagnosis and to evoke inherited bleeding disorders. Measurements of Von Willebrand factor (VWF) levels showed a marked reduction of VWF:RCo and a normal VWF:Ag, suggesting a type 2B Von Willebrand disease (VWD2B). Ristocetin-induced platelet aggregation could not be performed because of the very low platelet count. In the first case, after sequencing VWF exon 28, a heterozygous p.Leu1460Pro mutation was found consistent with VWD2B. In the second case, the genetic analysis of VWF exon 28 identified a homozygous mutation: p.Pro1337Leu confirming type VWD2B and also the p.Arg854Gln homozygous mutation in exon 20 confirming type 2N (ratio FVIII/VWF:Ag
Published: 2017
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5. Biological, clinical features and modelling of heterozygous variants of glycoprotein Ib platelet subunit alpha <scp> ( GP1BA ) </scp> and glycoprotein Ib platelet subunit beta ( <scp> GP1BB ) </scp> genes responsible for constitutional thrombocytopenia

Author: Fatema Dib, Agnès Quéméner, Sophie Bayart, Pierre Boisseau, Antoine Babuty, Marc Trossaërt, Marianne Sigaud, Catherine Ternisien, Nicolas Drillaud, Marion Eveillard, Benoit Guillet, Marie C. Béné, and Marc Fouassier
Subjects: Hematology
Published: 2022
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6. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), 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), University of Exeter, 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), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], 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 ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022
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7. Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence

Author: Annabelle Dupont, Christelle Soukaseum, Mathilde Cheptou, Frédéric Adam, Thomas Nipoti, Marc-Damien Lourenco-Rodrigues, Paulette Legendre, Valérie Proulle, Antoine Rauch, Charlotte Kawecki, Marijke Bryckaert, Jean-Philippe Rosa, Camille Paris, Catherine Ternisien, Pierre Boisseau, Jenny Goudemand, Delphine Borgel, Dominique Lasne, Pascal Maurice, Peter J. Lenting, Cécile V. Denis, Sophie Susen, and Alexandre Kauskot
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia.
Published: 2019
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8. Identification of new F8 deep intronic variations in patients with haemophilia A

Author: Pierre-Simon Rohrlich, Pierre Boisseau, Mathilde Fretigny, Amy Dericquebourg, Yohann Jourdy, Christine Vinciguerra, Catherine Ternisien, Ségolène Claeyssens, Anne Lienhart, and Claude Negrier
Subjects: Male, Haemophilia A, Alu element, 030204 cardiovascular system & hematology, Hemophilia A, Structural variation, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Genetic Predisposition to Disease, Gene, Genetics (clinical), Genetics, Messenger RNA, business.industry, Haplotype, Hematology, General Medicine, medicine.disease, Introns, RNA splicing, Female, business, 030215 immunology, Minigene
Abstract: Introduction With current molecular diagnosis, about 1 to 5% of haemophilia A (HA) patients remain genetically unresolved. In these cases, deep intronic variation or structural variation disrupting the F8 gene could be causal. Aim To identify the causal variation in four genetically unresolved mild-to-severe HA patients using an F8 mRNA analysis approach. Methods Ectopic F8 mRNA analysis was performed in four unrelated HA patients. An in vitro minigene assay was performed in order to confirm the deleterious splicing impact of each variation identified. Results In all probands, mRNA analysis revealed an aberrant splicing pattern, and sequencing of the corresponding intronic region found a deep intronic substitution. Two of these were new variations: c.2113+601G>A and c.1443+602A>G, while the c.143+1567A>G, found in two patients, has previously been reported. The c.1443+602A>G and the c.143+1567A>G variants both led to the creation of a de novo acceptor or donor splice site, respectively. Moreover, the c.143+1567A>G was found in 3/6 patients with genetically unresolved moderate HA registered in our laboratory. Haplotype analysis performed in all patients carrying the c.143+1567A>G variation suggests that this variation could be a recurrent variation. The c.2113+601G>A led to the exonization of a 122-bp antisense AluY element by increasing the strength of a pre-existing cryptic 5' splice site. For each point variation, in vitro splicing analysis confirmed its deleterious impact on splicing of the F8 transcript. Conclusion We identified three deep intronic variations, leading to an aberrant mRNA splicing process as HA causing variation.
Published: 2020
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9. The homozygous variant p.Gln1311* in exon 28 of VWF is associated with the development of alloantibodies in 3 unrelated patients with type 3 VWD

Author: Annie Harroche, Sophie Susen, Fanny Lassalle, Nicolas Duployez, Jenny Goudemand, Emmanuelle Jeanpierre, Céline Falaise, Christophe Zawadzki, Christine Biron-Andréani, Camille Paris, Antoine Rauch, and Pierre Boisseau
Subjects: Male, Adolescent, business.industry, MEDLINE, Exons, Hematology, General Medicine, von Willebrand Disease, Type 3, von Willebrand Diseases, Exon, Isoantibodies, von Willebrand Factor, Immunology, Humans, Medicine, Female, Child, business, Genetics (clinical)
Published: 2021
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10. Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

Author: Marc Fouassier, Nathalie Trillot, Claude Preudhomme, Véronique Tintiller, Coralie Derrieux, Elise Fournier, Céline Berthon, Nicolas Duployez, Camille Debord, Soraya Wuilleme, Valérie Soenen, Thomas Boyer, Louis Terriou, Camille Paris, Fanny Gonzales, Sophie Susen, Anne Lambilliotte, Pierre Boisseau, Wadih Abou Chahla, Hôpital Claude Huriez [Lille], CHU Lille, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille], Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU de Lille), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Régional de Traitement des Hémophiles [CHU Nantes], DESSAIVRE, Louise, and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, business.industry, Platelet disorder, [SDV]Life Sciences [q-bio], MEDLINE, Infant, Hematology, Middle Aged, Gastroenterology, Thrombocytopenia, [SDV] Life Sciences [q-bio], Internal medicine, Hematologic Neoplasms, medicine, Humans, Female, Genetic Predisposition to Disease, Blood Platelet Disorders, Baseline (configuration management), business, ComputingMilieux_MISCELLANEOUS, Germ-Line Mutation
Abstract: International audience
Published: 2020
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11. A new case of heterozygous variant of the <scp>GP</scp> 1 <scp>BB</scp> gene responsible for macrothrombocytopenia

Author: Benjamin Gillet, Catherine Ternisien, Marianne Sigaud, Marc Fouassier, Marc Trossaert, Pierre Boisseau, Marion Eveillard, Mathilde Giraud, Marie-Christine Béné, Camille Debord, and Antoine Babuty
Subjects: business.industry, Platelet disorder, Immunology, Medicine, Hematology, GP1BB Gene, Platelet membrane glycoprotein, business
Published: 2019
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12. An unexpected transmission of von Willebrand disease type 3: the first case of maternal uniparental disomy 12

Author: Pierre Boisseau, Mathilde Giraud, Catherine Ternisien, Agnès Veyradier, Edith Fressinaud, Armelle Lefrancois, Stéphane Bezieau, and Marc Fouassier
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2011
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13. Updated overview on von Willebrand disease: focus on the interest of genotyping

Author: Agnès Veyradier, Nathalie Itzhar-Baïkian, Pierre Boisseau, and Bérangère S. Joly
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Genotype, Genotyping Techniques, viruses, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Von Willebrand factor, hemic and lymphatic diseases, Von Willebrand disease, Medicine, Humans, Genotyping, Genetics, Sanger sequencing, Massive parallel sequencing, biology, business.industry, Hematology, medicine.disease, ADAMTS13, Most common inherited bleeding disorder, von Willebrand Diseases, 030220 oncology & carcinogenesis, biology.protein, symbols, business, circulatory and respiratory physiology, 030215 immunology
Abstract: Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative or qualitative defect of von Willebrand factor (VWF), a multimeric glycopr...
Published: 2019

14. Risk estimation of uniparental disomy of chromosome 14 or 15 in a fetus with a parent carrying a non‐homologous Robertsonian translocation. Should we still perform prenatal diagnosis?

Author: Sébastien Schmitt, Philippe Vago, Marie-Laure Maurin, Gregory Egea, Denise Molina Gomes, Emmanuelle Haquet, Marine Lebrun, Jacques Puechberty, François Vialard, Olivier Pichon, Perrine Malzac, Philippe Jonveaux, Martine Doco-Fenzy, Paul Kuentz, Sandra Chantot-Bastaraud, Kamran Moradkhani, Jean-Paul Bonnefont, Caroline Janel, Jean-Michel Dupont, Pierre Boisseau, Jean-Pierre Siffroi, Cédric Le Caignec, Anne-Laure Fauret-Amsellem, Damien Sanlaville, Chantal Missirian, Carole Goumy, Agnès Guichet, Marie-Christine Manca-Pellissier, Renaud Touraine, Laurence Cuisset, Pascale Saugier-Veber, Nicolas Gruchy, Houda Hamdi-Rozé, Bénédicte Duban-Bedu, Bruno Delobel, N. Joye, Isabelle Creveaux, Ines Harzallah, Frédéric Bilan, Philippe Gosset, Marie-Pierre Audrézet, Laboratoire de cytogénétique [CHU Nantes] (Service de génétique médicale), Centre hospitalier universitaire de Nantes (CHU Nantes), Depatment Biochemical Genetics, Université Paris Descartes - Paris 5 (UPD5), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Gatonero SA, Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Pontchaillou [Rennes], Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de cytogénétique prénatale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance Publique - Hôpitaux de Marseille (APHM), Espace éthique méditerranéen, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), 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), Laboratoire de Biochimie, Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Clermont-Ferrand, Histologie Embryologie Cytogénétique, Université d'Auvergne - Clermont-Ferrand I (UdA)-Faculté de Médecine, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies génétiques d'expression pédiatrique (U933), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre de Génétique Chromosomique, Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], CHI Poissy-Saint-Germain, Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), GHICL-Hôpital Saint Vincent de Paul, Hôpital Saint Vincent de Paul-GHICL, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie de la Reproduction, and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Robertsonian translocation, Chromosomal translocation, Prenatal diagnosis, 030105 genetics & heredity, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.disease_cause, Risk Assessment, Translocation, Genetic, Miscarriage, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, medicine, Humans, Genetics (clinical), Retrospective Studies, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 15, Fetus, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Obstetrics and Gynecology, Chromosome, Uniparental Disomy, medicine.disease, Uniparental disomy, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, business
Abstract: International audience; Objective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.
Published: 2019
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15. Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1

Author: Laetitia Monteil, Stéphanie Tomé, John Harting, Cheryl Heiner, Sandra Mercier, Yu-Chih Tsai, Pierre Boisseau, Mathilde Nizon, Janet Ziegle, Geneviève Gourdon, Laure de Pontual, Antoine Mangin, Cardiff University, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pacific Biosciences of California, CHU Toulouse [Toulouse], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Gourdon, Geneviève, and Centre de Recherche en Myologie
Subjects: Adult, Male, musculoskeletal diseases, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Genetic counseling, Locus (genetics), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030105 genetics & heredity, Biology, Myotonic dystrophy, Article, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, medicine, Humans, Myotonic Dystrophy, Physical and Theoretical Chemistry, Allele, myotonic dystrophy type 1, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Sequence (medicine), Genetics, long read sequencing, Mosaicism, Organic Chemistry, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Trinucleotide repeat disorder, medicine.disease, Molecular diagnostics, 3. Good health, Computer Science Applications, somatic mosaicism, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), lcsh:QD1-999, Female, Trinucleotide Repeat Expansion, interrupted CTG repeat expansion
Abstract: International audience; Myotonic dystrophy type 1 (DM1) is the most complex and variable trinucleotide repeat disorder caused by an unstable CTG repeat expansion, reaching up to 4000 CTG in the most severe cases. The genetic and clinical variability of DM1 depend on the sex and age of the transmitting parent, but also on the CTG repeat number, presence of repeat interruptions and/or on the degree of somatic instability. Currently, it is difficult to simultaneously and accurately determine these contributing factors in DM1 patients due to the limitations of gold standard methods used in molecular diagnostics and research laboratories. Our study showed the efficiency of the latest PacBio long-read sequencing technology to sequence large CTG trinucleotides, detect multiple and single repeat interruptions and estimate the levels of somatic mosaicism in DM1 patients carrying complex CTG repeat expansions inaccessible to most methods. Using this innovative approach, we revealed the existence of de novo CCG interruptions associated with CTG stabilization/contraction across generations in a new DM1 family. We also demonstrated that our method is suitable to sequence the DM1 locus and measure somatic mosaicism in DM1 families carrying more than 1000 pure CTG repeats. Better characterization of expanded alleles in DM1 patients can significantly improve prognosis and genetic counseling, not only in DM1 but also for other tandem DNA repeat disorders.
Published: 2021
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16. Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy

Author: Pascale Poullin, Eric Mariotte, Pierre Boisseau, Fouzia Zouiti, Ygal Benhamou, Lionel Galicier, Eric Rondeau, Agnès Veyradier, Emmanuel de Maistre, Alain Stepanian, Elie Azoulay, Paul Coppo, Pierre Perez, Yahsou Delmas, and François Provôt
Subjects: Male, HIV Infections, 030204 cardiovascular system & hematology, medicine.disease_cause, Gastroenterology, Autoimmunity, Cohort Studies, 0302 clinical medicine, Pregnancy, Risk Factors, Neoplasms, hemic and lymphatic diseases, Prevalence, Registries, First episode, Hematology, Middle Aged, Clopidogrel, ADAMTS13, Purpura, 030220 oncology & carcinogenesis, Female, France, medicine.symptom, medicine.drug, Adult, medicine.medical_specialty, Ticlopidine, Thrombotic microangiopathy, Fever, Genotype, Digestive System Diseases, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Infections, Autoimmune Diseases, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Autoantibodies, Purpura, Thrombocytopenic, Idiopathic, Transplantation, Purpura, Thrombotic Thrombocytopenic, business.industry, medicine.disease, Pregnancy Complications, Cross-Sectional Studies, Mutation, Immunology, Nervous System Diseases, Caplacizumab, business
Abstract: Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation.Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686.We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients).Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder.Assistance Publique-Hôpitaux de Paris.
Published: 2016
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17. Inherited Thrombotic Thrombocytopenic Purpura Revealed by Recurrent Strokes in a Male Adult: Case Report and Literature Review

Author: Bérangère S. Joly, Paul Coppo, Diane Beauvais, Pierre Boisseau, Christian Denier, Olivier Chassin, A. Ameri, Agnès Veyradier, Olivier Lambotte, Laura Venditti, Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Thrombotic microangiopathy, Heredity, Anemia, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Late onset, Polymorphism, Single Nucleotide, 03 medical and health sciences, Plasma, 0302 clinical medicine, Recurrence, Risk Factors, hemic and lymphatic diseases, medicine, Humans, Genetic Predisposition to Disease, Stroke, Pregnancy, Purpura, Thrombotic Thrombocytopenic, business.industry, Rehabilitation, medicine.disease, ADAMTS13, 3. Good health, Pedigree, Phenotype, Treatment Outcome, Mutation, Surgery, Neurology (clinical), Fresh frozen plasma, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). In this article, we describe the first case of a young male adult suffering from a hereditary TTP revealed by recurrent strokes, relapsing despite antiplatelet and anticoagulant therapy. Because of the persistent moderate thrombocytopenia, plasmatic ADAMTS13 activity was investigated and was found lower than 5% in the absence of anti-ADAMTS13 IgG. Direct sequencing of ADAMTS13 gene led to the diagnosis of Upschaw-Schulman syndrome (USS). Inherited TTP or USS is a rare autosomal recessive inherited disease leading to a severe deficiency of ADAMTS13 mostly beginning in childhood or in young female adult during pregnancy. Our patient was treated with fresh frozen plasma every 2 weeks. One year after diagnosis, he was free of neurological symptoms. Around 12 cases of inherited TTP diagnosed in adults (outside pregnancy) are described in literature. Only 4 of them exhibited a stroke. This case is the first late onset genetic TTP revealed by recurrent strokes, moderate thrombocytopenia without anemia.
Published: 2018
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18. ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw–Schulman Syndrome

Author: Yahsou Delmas, Bérangère S. Joly, Céline Garrec, Alain Stepanian, Pierre Boisseau, Nathalie Biebuyck, Paul Coppo, Elien Roose, Julien Hogan, Karen Vanhoorelbeke, François Provôt, and Agnès Veyradier
Subjects: MICROANGIOPATHIES, Protein Conformation, 030204 cardiovascular system & hematology, von Willebrand factor, Gastroenterology, Cohort Studies, ACTIVATION, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), hemic and lymphatic diseases, Genotype, ASSAY, MOLECULAR CHARACTERIZATION, Age of Onset, Child, FACTOR-CLEAVING PROTEASE, Hematology, ADAMTS13, Pedigree, 3. Good health, Phenotype, NATIONAL REGISTRY, Female, France, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Thrombotic microangiopathy, Adolescent, TTP, VON-WILLEBRAND-FACTOR, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, rare disease, Young Adult, 03 medical and health sciences, MISSENSE MUTATION, Internal medicine, medicine, Humans, THROMBOTIC THROMBOCYTOPENIC PURPURA, Upshaw–Schulman syndrome, Autoantibodies, Sequence (medicine), Polymorphism, Genetic, Science & Technology, Purpura, Thrombotic Thrombocytopenic, business.industry, Upshaw-Schulman syndrome, Infant, Newborn, Infant, medicine.disease, Peripheral Vascular Disease, Mutation, Cardiovascular System & Cardiology, Age of onset, business, Follow-Up Studies, 030215 immunology
Abstract: Background Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw–Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity Objective This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS. Patients and Methods All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS. Results Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation. Conclusion In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.
Published: 2018
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19. Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year ‘real-world’ experience

Author: M. Pacault, Pierre Boisseau, Laurent Ardillon, Marc Trossaert, Edith Fressinaud, O. Ribeyrol, Catherine Ternisien, A. Lefrançois, Marc Fouassier, and Marianne Sigaud
Subjects: Adult, Male, medicine.medical_specialty, Platelet Function Tests, Normal values, Medical care, Gastroenterology, ABO Blood-Group System, Ristocetin Cofactor, Von Willebrand factor, Predictive Value of Tests, hemic and lymphatic diseases, Internal medicine, von Willebrand Factor, Von Willebrand disease, medicine, Humans, Platelet, Genetics (clinical), biology, business.industry, PFA-100, Hematology, General Medicine, medicine.disease, Primary haemostasis, von Willebrand Diseases, Immunology, biology.protein, Female, business
Abstract: Summary The platelet function analyser (PFA-100) is a biological tool designed to explore primary haemostasis. This system has thus been widely demonstrated as reliable in detecting von Willebrand factor (VWF) deficiency. However, most studies were based on patients benefitting from regular medical care and accurate diagnosis, and it would seem probable that the results were somewhat optimistic, and do not reflect its performances in ‘real-world’ situations. We have chosen to study the reliability of PFA-100 for screening VWF ristocetin cofactor (VWF:RCo) deficiency. We retrospectively analysed the results (n = 6431) of 4027 patients referred to our centre between October 1997 and June 2013 and in whom PFA-Epi, PFA-ADP, and VWF:RCo activity had been evaluated. We studied the influence of blood group on the results and the performances of each method in a subgroup of 213 patients with genetically confirmed von Willebrand disease. We have shown that the PFA-100 system, in our experience, constitutes an excellent screening test for detecting VWF:RCo deficiency, whatever the clinical situation, in ‘real-world’ conditions. The negative predictive value (NPV), the positive predictive value, the sensitivity and the specificity were respectively: 0.98, 0.51, 0.98 and 0.40. When values adjusted for blood group are used, NPV and sensitivity are inferior to those using normal values which have not been adjusted for blood group. We have shown the PFA-100 method to be more efficient in screening for VWF deficiency than the VWF:RCo technique.
Published: 2015
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20. Use of a thrombopoietin receptor agonist in von Willebrand disease type 2B (p.V1316M) with severe thrombocytopenia and intracranial hemorrhage

Author: Marc Fouassier, Cécile V. Denis, O. Espitia, C. Agard, Catherine Ternisien, and Pierre Boisseau
Subjects: 0301 basic medicine, Mutation, Missense, Eltrombopag, von Willebrand Disease, Type 2, 030204 cardiovascular system & hematology, Benzoates, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Von Willebrand factor, hemic and lymphatic diseases, von Willebrand Factor, Thrombocytopathy, Von Willebrand disease, Humans, Medicine, Platelet, Thrombopoietin, Thrombopoietin receptor, biology, business.industry, Hematology, General Medicine, Middle Aged, medicine.disease, Thrombocytopenia, Hydrazines, 030104 developmental biology, Amino Acid Substitution, chemistry, Hemostasis, Immunology, biology.protein, Pyrazoles, Female, business, Intracranial Hemorrhages, Receptors, Thrombopoietin
Abstract: We present here a 63-year old woman with a long history of immune thrombocytopenia. She was hospitalized for a traumatic intracranial hemorrhage with thrombocytopenia. Following inefficient treatment of four platelet transfusions, immunoglobulins, and corticosteroids, we initiated treatment with a thrombopoietin (TPO) receptor agonist (eltrombopag 25 mg/d) with a good efficacy. Her mother and sister also had chronic thrombocytopenia. Clinical history, hemostasis results, and gene analysis revealed von Willebrand disease (VWD) type 2B with the mutation (c.3946G>A; p.V1316M), which combines a von Willebrand factor defect with severe thrombocytopenia, as well as a thrombocytopathy. The efficacy of TPO receptor agonists appears to counterbalance, at least to some extent, the thrombocytopathy associated with this mutation. As such, the use of TPO receptor agonists could represent an alternative therapeutic approach in cases of VWD type 2B with severe thrombocytopenia.
Published: 2016
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21. A new mutation of ANO 6 in two familial cases of Scott syndrome

Author: Pierre Boisseau, Mathilde Giraud, Stéphane Bézieau, Marie A. Gourlaouen, Marie C. Béné, Nelly Robillard, Marc Fouassier, Thomas Besnard, Patricia Talarmain, and Sinthuja Pachchek
Subjects: 0301 basic medicine, Genetics, 03 medical and health sciences, Inherited platelet disorder, 030104 developmental biology, Phospholipid scramblase, Scott syndrome, business.industry, New mutation, medicine, Hematology, medicine.disease, business
Published: 2016
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22. Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

Author: Laure Simon, Stéphane Bézieau, Sébastien Schmitt, Xenia Latypova, Madeleine Joubert, Mathilde Nizon, Claire Beneteau, Jean-Michel Vallat, Benjamin Cogné, Sandra Mercier, Bertrand Isidor, Yann Péréon, Marie Vincent, Sébastien Küry, Jean-Michel Liet, Marianne Coste, Pierre Boisseau, Jean-Marie Mussini, Catherine Larrose, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Limoges, and Hôpital Femme Mère Enfant
Subjects: Foot Deformities, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, neuropathies, Cell Adhesion Molecules, Neuronal, Mutation, Missense, Short Report, Motor nerve, Biology, Compound heterozygosity, Frameshift mutation, 03 medical and health sciences, Myelin, 0302 clinical medicine, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Axon, Myelin Sheath, Genetics (clinical), congenita, Arthrogryposis, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Siblings, Homozygote, Infant, Newborn, Infant, Pathophysiology, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, factor, nervous system, Muscle Hypotonia, genetic, medicine.symptom, 030217 neurology & neurosurgery
Abstract: International audience; Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.
Published: 2016
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23. Two novel variants of uncertain significance in GP9 associated with Bernard–Soulier syndrome: Are they true mutations?

Author: G. Landeau, Marc Fouassier, S. Bezieau, Marie C. Béné, Camille Debord, Pierre Boisseau, C. Thomas, B. Pan Petesch, M. Giraud, M. Sigaud, Marion Eveillard, Agnès Quéméner, P. Talarmain, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service d'Hématologie Biologique [CHU Nantes], Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Régional de Traitement des Hémophiles [CHU Nantes], Centre Régional de Traitement des Hémophiles [CHU Brest], Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Models, Molecular, Genotype, Protein Conformation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bernard–Soulier syndrome, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Von Willebrand factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glycoprotein complex, Thrombocytopathy, medicine, Humans, Platelet, Alleles, Genetic Association Studies, chemistry.chemical_classification, biology, GP9, Bernard-Soulier Syndrome, Computational Biology, Genetic Variation, Hematology, General Medicine, Sequence Analysis, DNA, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, chemistry, Platelet Glycoprotein GPIb-IX Complex, Child, Preschool, Immunology, Mutation, biology.protein, Anisocytosis, Female, Glycoprotein, Biomarkers, 030215 immunology, Rare disease
Abstract: International audience; Bernard–Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x10[9]/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets.
Published: 2017
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24. Molecular genetic techniques

Author: Pierre Boisseau
Subjects: Hematology
Abstract: GeneralitesNomenclatureLe gene du facteur Willebrand est note, selon la nomenclature internationale du HUGO Gene Nomenclature Committee (HGNC), VWF (OMIM 613160). Il est situe sur le chromosome 12 (12p13.3), s’etend sur 178 kb et comporte cinquante-deux exons qui representent 9 kb d’ADN complementaire (ADNc), ce qui fait de lui un grand gene. Il est donc necessaire de bien determiner la strategie du diagnostic moleculaire afin d’eviter des etudes superflues. Cette strategie [...]
Published: 2014
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25. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura

Author: Marie, Moatti-Cohen, Céline, Garrec, Martine, Wolf, Pierre, Boisseau, Lionel, Galicier, Elie, Azoulay, Alain, Stepanian, Yahsou, Delmas, Eric, Rondeau, Stéphane, Bezieau, Paul, Coppo, Agnès, Veyradier, and Marc, Buffet
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Genotype, Immunology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Congenital Thrombotic Thrombocytopenic Purpura, Polymorphism, Single Nucleotide, Biochemistry, Cohort Studies, Diagnosis, Differential, Pregnancy, hemic and lymphatic diseases, medicine, Coagulopathy, Humans, Registries, Upshaw–Schulman syndrome, Purpura, Thrombotic Thrombocytopenic, Vascular disease, business.industry, Pregnancy Complications, Hematologic, Genetic Diseases, Inborn, Cell Biology, Hematology, respiratory system, medicine.disease, ADAMTS13, Pedigree, Surgery, ADAM Proteins, Treatment Outcome, Mutation, Female, France, Age of onset, business, Follow-Up Studies
Abstract: Pregnancy may be complicated by a rare but life-threatening disease called thrombotic thrombocytopenic purpura (TTP). Most cases of TTP are due to an acquired autoimmune or hereditary (Upshaw-Schulman syndrome [USS]) severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13). In the present study, we performed a cross-sectional analysis of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000-2010 to identify all women who were pregnant at their initial TTP presentation. Among 592 adulthood-onset TTP patients with a severe ADAMTS13 deficiency, 42 patients with a pregnancy-onset TTP were included. Surprisingly, the proportion of USS patients (n = 10 of 42 patients [24%]; confidence interval, 13%-39%) with pregnancy-onset TTP was much higher than that in adulthood-onset TTP in general (less than 5%) and was mostly related to a cluster of ADAMTS13 variants. In the present study, subsequent pregnancies in USS patients not given prophylaxis were associated with very high TTP relapse and abortion rates, whereas prophylactic plasmatherapy was beneficial for both the mother and the baby. Pregnancy-onset TTP defines a specific subgroup of patients with a strong genetic background. This study was registered at www.clinicaltrials.gov as number NCT00426686 and at the Health Authority, French Ministry of Health, as number P051064.
Published: 2012
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26. De novo duplication and deletions at 7q in a three-generation family

Author: Bertrand Isidor, Pierre Boisseau, Cédric Le Caignec, Luis A. Pérez-Jurado, Olivier Pichon, Annaig Briand, Olaya Villa, and Damien Poulain
Subjects: Male, Comparative Genomic Hybridization, business.industry, Karyotype, Facies, Trisomy, Computational biology, Biology, Pedigree, Text mining, Gene duplication, Genetics, Humans, Family, Female, Chromosome Deletion, Child, business, Chromosomes, Human, Pair 7, In Situ Hybridization, Fluorescence, Genetics (clinical)
Published: 2012
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27. A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis

Author: Edith Fressinaud, Emmanuelle Jeanpierre, Eric Van Belle, Cécile Lavenu-Bombled, Christophe Zawadzki, Annie Borel-Derlon, Antoine Rauch, Pierre Boisseau, Peter J. Lenting, André Vincentelli, Jenny Goudemand, Catherine Ternisien, Claudine Caron, Sophie Susen, Alexandre Ung, Agnès Veyradier, Flavien Vincent, Camille Paris, and Sylvie Hermoire
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Proteolysis, Mutation, Missense, Context (language use), Enzyme-Linked Immunosorbent Assay, von Willebrand Disease, Type 2, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Acquired von Willebrand syndrome, Von Willebrand factor, hemic and lymphatic diseases, Internal medicine, von Willebrand Factor, medicine, Von Willebrand disease, Humans, medicine.diagnostic_test, biology, business.industry, Case-control study, Hematology, Aortic Valve Stenosis, medicine.disease, Stenosis, von Willebrand Diseases, Amino Acid Substitution, 030220 oncology & carcinogenesis, Aortic valve stenosis, Case-Control Studies, Immunology, biology.protein, Heart-Assist Devices, Protein Multimerization, business
Abstract: SummaryVon Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speeddependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWDpatients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWFproteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.Supplementary Material to this article is available online at www.thrombosis-online.com.
Published: 2015

28. Incidence of obstetrical thrombotic thrombocytopenic purpura in a retrospective study within thrombocytopenic pregnant women. A difficult diagnosis and a treatable disease

Author: Sébastien Helou, Paul Coppo, Dominique Carles, Fanny Pelluard, Jacques Horovitz, Agnès Veyradier, Pierre Boisseau, Yahsou Delmas, Pierre Chabanier, Christian Combe, Anne Ryman, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Centre de compétences des microangiopathies thrombotiques, Université Bordeaux Segalen - Bordeaux 2, pôle gynécologie-obstétrique et médecine foetale, Service d'hémostase spécialisée, Service d'anatomie pathologique, Service de génétique médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des microangiopathies thrombotiques [CHU Saint-Antoine] (Cnr-mat), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Pediatrics, HELLP syndrome, medicine.medical_treatment, Perinatal Death, Placenta, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, 030204 cardiovascular system & hematology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, hemic and lymphatic diseases, Obstetrics and Gynaecology, Medicine, Humans, Young adult, Upshaw–Schulman syndrome, Retrospective Studies, Purpura, Thrombotic Thrombocytopenic, business.industry, Platelet Count, Upshaw-Schulman syndrome, Incidence, Pregnancy Complications, Hematologic, Infant, Newborn, Pregnancy Outcome, Obstetrics and Gynecology, Retrospective cohort study, Plasmapheresis, Thrombotic Thrombocytopenic Purpura, medicine.disease, Thrombocytopenia, 3. Good health, Surgery, ADAM Proteins, Parity, ADAMTS-13 deficiency, 030220 oncology & carcinogenesis, Etiology, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: International audience; BackgroundThrombotic thrombocytopenic Purpura (TTP) defined as ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13) activity
Published: 2015
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29. A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Author: Chloé Bellocq, Hervé Le Marec, Isabelle Baró, Denis Escande, Bénédicte Louérat-Oriou, Ronald Wilders, Jean-Jacques Schott, Pierre Boisseau, and Medical Biology
Subjects: Male, Threonine, Proline, Long QT syndrome, hERG, Mutant, Torsades de pointes, Pharmacology, medicine.disease_cause, QT interval, Ventricular action potential, chemistry.chemical_compound, Chlorocebus aethiops, medicine, Animals, Humans, Cation Transport Proteins, Mutation, Alanine, biology, Chemistry, Arrhythmias, Cardiac, Valine, medicine.disease, Amino Alcohols, Ether-A-Go-Go Potassium Channels, Pedigree, Electrophysiology, Antitussive Agents, Long QT Syndrome, Potassium Channels, Voltage-Gated, COS Cells, biology.protein, Molecular Medicine, Clobutinol
Abstract: QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K(+) current with a half-maximum block concentration of 2.9 microM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K(+) current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a approximately -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes".
Published: 2004
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30. Novel SCN5A Mutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family

Author: Hervé Le Marec, Jean Christophe Chevallier, Isabelle Baró, F. Kyndt, Denis Escande, Franck Potet, Sophie Demolombe, Jean-Jacques Schott, Pierre Boisseau, Vincent Probst, and Jean Paul Moisan
Subjects: Male, medicine.medical_specialty, Heart block, Recombinant Fusion Proteins, DNA Mutational Analysis, Green Fluorescent Proteins, Mutation, Missense, Sodium Channels, Membrane Potentials, NAV1.5 Voltage-Gated Sodium Channel, Electrocardiography, Heart Conduction System, Physiology (medical), Internal medicine, Cardiac conduction, medicine, Animals, Humans, Missense mutation, Brugada syndrome, Family Health, Microscopy, Confocal, Bundle branch block, business.industry, Sodium channel, DNA, Syndrome, Right bundle branch block, medicine.disease, Pedigree, Luminescent Proteins, Heart Block, Endocrinology, Microscopy, Fluorescence, COS Cells, Mutation, Mutation (genetic algorithm), Cardiology, Female, France, Cardiology and Cardiovascular Medicine, business
Abstract: Background — The SCN5A gene encoding the human cardiac sodium channel α subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). Methods and Results — In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na + current but normal protein trafficking. Conclusions — We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.
Published: 2001
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31. A faster strategy for prenatal diagnosis of fragile X syndrome

Author: Stéphane Bézieau, Sébastien Schmitt, Pierre Boisseau, Jean-Marie Rival, M. Giraud, and J. Hary
Subjects: Genetics, medicine.medical_specialty, Genetic counseling, Obstetrics and Gynecology, Prenatal diagnosis, Chromosome Fragility, Biology, medicine.disease, FMR1, Fragile X syndrome, chemistry.chemical_compound, chemistry, medicine, Neonatology, Gene, Genetics (clinical), DNA
Published: 2010
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32. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders

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

Author: Audrey Migraine, Olivier Pichon, Elise Launay, Elodie Lainey, Marc David Leclair, Guylène Le Meur, Thomas Le Francois, Boris Keren, Albert David, Emmanuelle Caldagues, Carole Conti, Cédric Le Caignec, Pierre Boisseau, Yanick J. Crow, and Bertrand Isidor
Subjects: Male, medicine.medical_specialty, Pathology, Microcephaly, Intestinal Atresia, Dwarfism, Short stature, Duodenal atresia, Internal medicine, Genetics, medicine, Feingold syndrome, Humans, Abnormalities, Multiple, Coats' disease, Genetics (clinical), Brain Diseases, business.industry, Leukodystrophy, Preaxial polydactyly, Calcinosis, Micropenis, Exudates and Transudates, Syndrome, medicine.disease, Polydactyly, Endocrinology, Phenotype, Child, Preschool, Retinal Telangiectasis, Duodenal Obstruction, medicine.symptom, Genital Diseases, Male, business, Tomography, X-Ray Computed, Penis
Abstract: The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17?92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome. � 2013 Wiley Periodicals, Inc.
Published: 2012

34. ADAM15 to α5β1 integrin switch in colon carcinoma cells: a late event in cancer progression associated with tumor dedifferentiation and poor prognosis

Author: Aude Colson, Jean-François Mosnier, Claire Toquet, Christelle Volteau, Didier Merlin, Stéphane Bézieau, Anne Jarry, Christian L. Laboisse, and Pierre Boisseau
Subjects: Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, ADAM15, Epithelial-Mesenchymal Transition, Colorectal cancer, Integrin, Down-Regulation, Adenocarcinoma, medicine, Humans, Epithelial–mesenchymal transition, RNA, Messenger, Intestinal Mucosa, Promoter Regions, Genetic, Aged, Aged, 80 and over, biology, Cell adhesion molecule, Integrin alpha3beta1, Cancer, Membrane Proteins, Cell Differentiation, DNA Methylation, Middle Aged, medicine.disease, Cadherins, ADAM Proteins, Oncology, DNA methylation, Cancer cell, Colonic Neoplasms, biology.protein, Disease Progression, Female, Microsatellite Instability, Integrin alpha5beta1
Abstract: ADAM15, a member of the A Disintegrin And Metalloproteinase (ADAM) family, is a membrane protein containing an adhesion domain that binds to α5β1 integrin through a unique RGD domain. ADAM15, expressed by human normal colonocytes, is involved in epithelial wound healing and tissue remodeling in inflammatory bowel disease. The aims of our study were (i) to analyze ADAM15 expression in a series of colon carcinomas and paired normal mucosa and (ii) to integrate the spatial relationship of ADAM15 with its binding partners α5β1 integrin, a mesenchymal marker, as well as with other adhesion molecules, α3β1 integrin and E-cadherin. A series of 94 colon carcinomas of the non other specified category were graded according to the World Health Organization classification. Immunohistochemistry was performed on frozen tissue sections using antibodies directed to ADAM15, α5β1 and α3β1 integrins, and E-cadherin. ADAM15 was quantified at the mRNA level. Finally, promoter methylation of ADAM15 was examined as well as the microsatellite instability status (MSS/MSI). Thirty-six percent of colorectal carcinomas displayed a reduced expression of ADAM15 in cancer cells, confirmed at the mRNA level in most cases, without promoter methylation. ADAM15 down-regulation was associated with histologically poorly differentiated carcinomas. In addition, it was associated with the acquisition of α5β1 by cancer cells and down-regulation of α3β1 integrin and E-cadherin. Finally this profile that includes characteristic of epithelial to mesenchymal transition is a late progression event of colon cancer with a poor prognosis.
Published: 2010

35. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening

Author: Brigitte Simon-Bouy, Georges, Bénédicte Gérard, Harriet Corvol, Emmanuelle Girodon, Raphaele Nove-Josserand, Catherine Costa, Michael A. Morris, Delphine Feldmann, Annick Clement, G. Bellis, Sylvie Leroy, Christine Binquet, J. Leclerc, A Iron, Laurence Faivre, M Roussey, Anne Munck, Mireille Claustres, F. Huet, Elodie Gautier, Claire Bonithon-Kopp, E. Houssin, Emmanuelle Génin, Isabelle Sermet-Gaudelus, S. Perez-Martin, Eric Bieth, Pierre Boisseau, Cabet-Bey F, Christine Clavel, J. Flori, Dominique Hubert, N. Wizla, Marie-Pierre Audrézet, Gabriel Bellon, A. Haloun, Guy Lalau, d'Acremont G, T Bienvenu, Christel Thauvin-Robinet, Gilles Rault, C. Alberti-Boulmé, Claude Férec, Michel Goossens, and R. Medina
Subjects: medicine.medical_specialty, Heterozygote, Cystic Fibrosis, Genetic counseling, Population, FRANCE, Cystic Fibrosis Transmembrane Conductance Regulator, Genetic Counseling, Penetrance, Kaplan-Meier Estimate, Compound heterozygosity, Cystic fibrosis, Gastroenterology, Neonatal Screening, Internal medicine, CYSTIC_FIBROSIS, Genotype, Genetics, Medicine, Humans, Allele, education, Genetics (clinical), Newborn screening, education.field_of_study, business.industry, Infant, Newborn, medicine.disease, SCREENING, Cross-Sectional Studies, Phenotype, Mutation, business
Abstract: Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p R117H), on either intron 8 T5 or T7 background, and F508del (p F508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p F508del was 1.06%, p R117H;T7 0.27% and p R117H;T5 ,0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes .
Published: 2009

36. Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation

Author: G. Di Virgilio, E. Lamy, Jacques S. Beckmann, Stéphane Bézieau, Sébastien Jacquemont, M. Sevin, François Vingerhoets, P. Renou, Laurent Pasquier, Pierre Boisseau, Jean-Marie Rival, Martine Vercelletto, S. Bergman, Z. Kutalik, and Philippe Damier
Subjects: Male, Pediatrics, medicine.medical_specialty, Ataxia, Population, Penetrance, Neuropsychological Tests, Fragile X Mental Retardation Protein, Double-Blind Method, Genetics, medicine, Dementia, Humans, Cognitive decline, education, Genetics (clinical), Alleles, education.field_of_study, business.industry, Cognitive disorder, DNA, Middle Aged, medicine.disease, FMR1, Fragile X syndrome, Blotting, Southern, Fragile X Syndrome, medicine.symptom, business, Cognition Disorders, Trinucleotide Repeat Expansion
Abstract: Background: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognized and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counseling. Methods: The Mattis Dementia Rating Scale (MDRS) was administered in a double-blind fashion to 74 males aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score ≤ 123 on the MDRS. Results: Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p
Published: 2009

37. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase

Author: Sylvie Tuffery-Giraud, Rabah Ben Yaou, Marie-Pierre Moizard, Jean-Claude Kaplan, Mireille Claustres, Laurence Michel-Calemard, Pierre Boisseau, Anne Guiochon-Mantel, Mireille Cossée, Christophe Philippe, Isabelle Creveaux, Christophe Béroud, Philippe Khau Van Kien, Martine Blayau, François-Olivier Desmet, Berengere de Martinville, Véronique Humbertclaude, Eric Bieth, Jamel Chelly, Nicole Monnier, Dalil Hamroun, Rafaëlle Bernard, 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), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de biologie et pathologie Est, Hospices Civils de Lyon (HCL), 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de Biochimie, Université d'Auvergne - Clermont-Ferrand I (UdA), Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [Purpan], CHU Toulouse [Toulouse], Laboratoire de Biochimie et Génétique Moléculaire, Human Molecular Genetics, Laboratoire de génétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, 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], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: musculoskeletal diseases, Male, Heterozygote, Genotype, Duchenne muscular dystrophy, Knowledge Bases, Nonsense mutation, Biology, computer.software_genre, Bioinformatics, Genotype phenotype, Dystrophin, 03 medical and health sciences, 0302 clinical medicine, RNA analysis, Databases, Genetic, Genetics, medicine, Humans, Point Mutation, In patient, Genetics (clinical), 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Database, Chromosome Breakage, Exons, medicine.disease, Introns, 3. Good health, Muscular Dystrophy, Duchenne, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Mutation, National database, Female, France, RNA Splice Sites, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genetic diagnosis, computer, 030217 neurology & neurosurgery, Software
Abstract: International audience; UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.
Published: 2009
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38. Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma

Author: Martine Le Cunff, Caroline Thomas, Michelle Boceno, Pierre Boisseau, Bertrand Isidor, Albert David, Cédric Le Caignec, and Jean-Marie Rival
Subjects: Candidate gene, Monosomy, Biology, Infant, Newborn, Diseases, Neuroblastoma, Gene mapping, Intellectual Disability, Gene duplication, Genetics, medicine, Humans, Multiplex ligation-dependent probe amplification, Genetics (clinical), In Situ Hybridization, Fluorescence, medicine.diagnostic_test, Infant, Newborn, General Medicine, Telomere, medicine.disease, Chromosome Banding, Chromosomes, Human, Pair 1, Female, Chromosome Deletion, Comparative genomic hybridization, Fluorescence in situ hybridization
Abstract: Monosomy 1p36 is one of the most frequent subtelomeric microdeletion syndromes characterized by distinct craniofacial features and developmental delay/mental retardation. Other common symptoms include hypotonia, seizures, brain abnormalities, visual, auditory and heart defects. Neuroblastoma is a rare feature since to our knowledge only two patients with “pure” 1p36 deletion have been described. We report on a child with developmental delay and facial dysmorphy who developed neuroblastoma at 1 month of age. No primary site outside of the liver could be demonstrated and the tumour regressed spontaneously. Standard karyotyping was normal while subtelomeric screening using Multiplex Ligation-dependent Probe Amplification (MLPA) method revealed a constitutional de novo subtelomeric 1p36 deletion. Subsequent Agilent 244K oligonucleotide array-based comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis showed a complex 1p36.3 deletion/duplication rearrangement. Among the best candidate genes predisposing to the development of neuroblastoma located in 1p36, the AJAP1 gene is the only gene present in the duplication while CHD5 , TNFRSF25 and CAMTA1 are located outside of the rearrangement. Therefore, a gene-dosage effect involving a gene located in the duplication including AJAP1 might explain the neuroblastoma observed in our patient. The rearrangement might equally interfere with the expression of a gene located outside of it (including CHD5 located 1 Mb away from the rearrangement) playing a role in the tumorigenesis. In conclusion, this study illustrates the complexity of such rearrangement characterized by array CGH and strengthens that constitutional 1p36.3 rearrangement predisposes to the development of neuroblastoma.
Published: 2007

39. Inherited 18q23 duplication in a fetus with multiple congenital anomalies

Author: Albert David, Madeleine Joubert, Cédric Le Caignec, Norbert Winer, Pierre Boisseau, Catherine Fallet, Michelle Boceno, Bertrand Isidor, and Jean Marie Rival
Subjects: Chromosome Aberrations, congenital, hereditary, and neonatal diseases and abnormalities, Corpus Callosum Agenesis, Lissencephaly, Nucleic Acid Hybridization, General Medicine, Anatomy, Biology, medicine.disease, Fetal Diseases, Karyotyping, Gene duplication, Genetics, Hypoplastic aortic arch, Pierre Robin syndrome, medicine, Humans, Abnormalities, Multiple, Multiplex ligation-dependent probe amplification, Abnormality, Chromosomes, Human, Pair 18, Cerebellar hypoplasia, Genetics (clinical), In Situ Hybridization, Fluorescence
Abstract: We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.
Published: 2007

40. 355 Family testing: the 17-year experience of Brittany (western France)

Author: H. Journel, Martine Blayau, M.-P. Audrézet, Virginie Scotet, I. Duguépéroux, Claude Férec, Philippe Parent, and Pierre Boisseau
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Family medicine, Pediatrics, Perinatology and Child Health, medicine, Pediatrics, Perinatology, and Child Health, medicine.disease, business, Cystic fibrosis
Published: 2007
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41. 372* Outcome of the pregnancies with an echogenic bowel detected by ultrasonography: the 15 year-experience of Brittany (western France)

Author: Virginie Scotet, Claude Férec, I. Duguépéroux, Martine Blayau, Philippe Parent, M.-P. Audrézet, Pierre Boisseau, and H. Journel
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, General surgery, Pediatrics, Perinatology and Child Health, medicine, Echogenic Bowel, Pediatrics, Perinatology, and Child Health, Ultrasonography, business, medicine.disease, Cystic fibrosis, Surgery
Published: 2007
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42. Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy

Author: Dalil Hamroun, Michel Pagès, Véronique Humbertclaude, Marie-Antoinette Voelckel, Christophe Béroud, Masafumi Matsuo, Luis Garcia, Sylvie Tuffery-Giraud, Mireille Claustres, Marie-Pierre Moizard, Nicole Monnier, Martine Blayau, Pierre Boisseau, Mireille Cossée, Olivier Danos, François Rivier, Laurence Michel Calemard, Christophe Philippe, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Kobe University Graduate School of Medicine, Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie, Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de génétique, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Département de Neurologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neuropédiatrie, Centre de recherche et d'applications sur les thérapies géniques (CRATG), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)-Généthon, Association Française contre les Myopathies, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Roux-Buisson, Nathalie
Subjects: Male, Duchenne muscular dystrophy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, Exon, 0302 clinical medicine, MESH: Oligonucleotides, Antisense, MESH: Child, MESH: Sequence Analysis, RNA, MESH: Codon, Nonsense, Muscular dystrophy, Child, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, MESH: Middle Aged, biology, Exons, Middle Aged, MESH: Sequence Deletion, Phenotype, 3. Good health, Codon, Nonsense, Dystrophin, MESH: Computational Biology, Adult, musculoskeletal diseases, muscular dystrophy, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, dystrophin, Open Reading Frames, 03 medical and health sciences, MESH: Dystrophin, BMD, DMD, medicine, MESH: Muscular Dystrophy, Duchenne, Humans, multiple-exon skipping, Gene, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Sequence Analysis, RNA, Computational Biology, MESH: Adult, Oligonucleotides, Antisense, MESH: Open Reading Frames, medicine.disease, Exon skipping, MESH: Male, Muscular Dystrophy, Duchenne, Open reading frame, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, MESH: Exons, 030217 neurology & neurosurgery
Abstract: International audience; Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.
Published: 2007
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43. Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation

Author: Frederic Sacher, Jean-Michel Nguyen M.D., Jean-Jacques Schott, Pierre Boisseau, Philipe Mabo, Dominique Babuty, Hervé Le Marec, Vincent Probst, Jacques Mansourati, Denis Escande, Sabine Pattier, Jacques Victor, Marie Allouis, 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Optimisation des régulations physiologiques (ORPHY (EA 4324)), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), PIMESP, Université de Nantes (UN), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut du thorax
Subjects: Male, 030204 cardiovascular system & hematology, Sodium Channels, MESH: Linear Models, MESH: Heart Conduction System, Electrocardiography, 0302 clinical medicine, MESH: Syndrome, Brugada syndrome, 0303 health sciences, MESH: Middle Aged, Left bundle branch block, Syndrome, Right bundle branch block, Middle Aged, 3. Good health, Pedigree, Phenotype, Mutation (genetic algorithm), Cardiology, Disease Progression, MESH: Disease Progression, Female, France, Cardiology and Cardiovascular Medicine, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, MESH: Mutation, Adolescent, Heart block, MESH: Pedigree, MESH: Phenotype, MESH: Sodium Channels, 03 medical and health sciences, QRS complex, Heart Conduction System, Physiology (medical), Internal medicine, MESH: Heart Block, Cardiac conduction, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, cardiovascular diseases, 030304 developmental biology, MESH: Adolescent, Family Health, MESH: Humans, Bundle branch block, business.industry, MESH: Adult, medicine.disease, MESH: Male, MESH: Electrocardiography, MESH: France, Heart Block, Mutation, MESH: Family Health, Linear Models, business, MESH: Female
Abstract: Progressive Conduction Defects in Brugada Syndrome. Introduction: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenegre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. Methods and Results: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. Conclusion: The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenegre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects.
Published: 2006
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44. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child

Author: Hervé Le Marec, Stephane Evain, Vincent Probst, Veronique Gournay, Allouis Marie, Jean-Jacques Schott, and Pierre Boisseau
Subjects: Quinidine, Tachycardia, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Bundle-Branch Block, DNA Mutational Analysis, Muscle Proteins, Sodium Channels, Syncope, NAV1.5 Voltage-Gated Sodium Channel, Electrocardiography, Heart Rate, Physiology (medical), Internal medicine, Heart rate, medicine, Humans, cardiovascular diseases, Idiopathic ventricular fibrillation, Normal heart, Brugada syndrome, Monomorphic Ventricular Tachycardia, medicine.diagnostic_test, business.industry, DNA, Syndrome, medicine.disease, Child, Preschool, Mutation, cardiovascular system, Cardiology, Tachycardia, Ventricular, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Anti-Arrhythmia Agents, medicine.drug, Follow-Up Studies
Abstract: Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3-year-old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T-->C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months.
Published: 2006

45. Le principe de subsidiarité et les constitutions des nouveaux membres de l’Union européenne : les exemples de la Pologne et de la République Tchèque

Author: Pierre Boisseau
Abstract: Aborder les constitutions des deux Etats sujets de l’etude sous l’angle du principe de subsidiarite peut sembler une entreprise quelque peu audacieuse. En effet, la subsidiarite n’est pas mentionnee explicitement dans les textes concernes. Neanmoins on la trouve en filigrane. En effet, le constituant a eu la lourde tâche d’inscrire l’Etat post-socialiste dans la modernite. Et, dans ce but, il s’est en quelque sorte efforce de le mettre en ordre de marche pour qu’il puisse integrer l’Union eur...
Published: 2005
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46. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome

Author: Thomas Wichter, Pierre Boisseau, Lars Eckardt, Eric Schulze Bahr, Vincent Probst, Christian Wolpert, Günter Breithardt, Dirk Böcker, Herve LeMarec, Achim Heinecke, Jeroen P.P. Smits, Arthur A.M. Wilde, Rainer Schimpf, Martin Borggrefe, ACS - Amsterdam Cardiovascular Sciences, and Cardiology
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Bundle-Branch Block, Asymptomatic, Sudden death, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, Electrocardiography, Physiology (medical), Internal medicine, medicine, Humans, cardiovascular diseases, Child, Aged, Brugada syndrome, Aged, 80 and over, Fibrillation, medicine.diagnostic_test, business.industry, ST elevation, Middle Aged, Prognosis, medicine.disease, Electric Stimulation, Mutation, Ventricular fibrillation, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies, Sodium Channel Blockers
Abstract: Background— Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death as a result of ventricular fibrillation. Controversy exists with regard to risk stratification and therapeutic management, particularly in asymptomatic individuals. Methods and Results— A total of 212 individuals (mean age, 45±6 years) with a type 1 Brugada ECG pattern were studied. Of these, 123 (58%) were asymptomatic, 65 (31%) had ≥1 syncope of unknown origin, and 24 (11%) had to be resuscitated because of ventricular fibrillation. In 125 individuals (59%), a spontaneous type 1 ECG was recorded. In the remaining, drug challenge with a class I antiarrhythmic agent unmasked a Brugada ECG. The mean ST elevation was 2.3±1.2 mm in symptomatic patients and 1.9±1.5 mm in asymptomatic individuals ( P =0.04). During a mean follow-up of 40±50 months, 4 of the 24 patients (17%) with aborted sudden cardiac death and 4 of 65 (6%) with a prior syncope had a recurrent arrhythmic event, whereas only 1 of 123 asymptomatic individuals (0.8%) had a first arrhythmic event. Four of 9 patients with arrhythmic events during follow-up were not inducible during programmed electrical stimulation. A previous history of aborted sudden death or syncope and the presence of a spontaneous type 1 ECG were predictors of adverse outcome. Conclusions— The present study reports data on a large population of individuals with a type 1 Brugada ECG pattern with the longest follow-up reported so far. A very low incidence of severe arrhythmic events, particularly in asymptomatic individuals, was found during follow-up. In the presence of very few arrhythmic events on follow-up, programmed electrical stimulation showed very little accuracy in predicting outcome.
Published: 2005

47. Chapitre II. L'adhésion des Pays d'Europe Centrale et Orientale à l'Union Européenne : aboutissement de la transition démocratique

Author: Pierre Boisseau
Published: 2004
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48. An unexpected transmission of von Willebrand disease type 3: the first case of maternal uniparental disomy 12

Author: Marc Fouassier, Stéphane Bézieau, Edith Fressinaud, Agnès Veyradier, Armelle Lefrancois, Mathilde Giraud, Pierre Boisseau, and Catherine Ternisien
Subjects: Genetics, Von Willebrand disease type 3, congenital, hereditary, and neonatal diseases and abnormalities, Chromosome, Hematology, Biology, medicine.disease, Maternal uniparental disomy, Von Willebrand factor, hemic and lymphatic diseases, Von Willebrand disease, medicine, biology.protein, Letters to the Editor, circulatory and respiratory physiology
Abstract: Von Willebrand disease (VWD) is an inherited heterogeneous bleeding disorder caused by either a quantitative and/or qualitative defect of von Willebrand factor (VWF).[1][1],[2][2] It is encoded by a gene located on chromosome 12p13.3 composed of 52 exons.[3][3] VWD type 3 involves a virtually
Published: 2011
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49. Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype

Author: Isabelle Baró, Gilles Lande, F. Kyndt, Pierre Boisseau, J.-C. Pony, D. Chabannes, Denis Escande, and H. Le Marec
Subjects: Adult, Male, medicine.medical_specialty, Potassium Channels, Heart disease, Adolescent, Genotype, Heart block, Long QT syndrome, QT interval, Internal medicine, medicine, Humans, cardiovascular diseases, Circadian rhythm, Longitudinal Studies, Child, Aged, Family Health, medicine.diagnostic_test, KCNQ Potassium Channels, business.industry, Middle Aged, medicine.disease, Penetrance, Long QT Syndrome, Endocrinology, Phenotype, Potassium Channels, Voltage-Gated, Child, Preschool, Ambulatory, KCNQ1 Potassium Channel, Mutation, Cardiology, Electrocardiography, Ambulatory, Female, France, Cardiology and Cardiovascular Medicine, business, Electrocardiography, Follow-Up Studies
Abstract: Aims In families with the long QT syndrome penetrance may be low: up to 70% of gene carriers may have a normal QTc interval. These patients require therapy, similar to that in those with longer QTc intervals, but identifying them, using molecular analysis, is difficult to apply on a large scale. A large French family affected by the long QT1 syndrome was followed-up over a 25-year period. In adult males but not in females, the QTc interval normalized after puberty. We aimed to find clinical criteria, based on ambulatory ECG recordings so that we could improve diagnosis in affected members with a normal QTc. Methods and Results Linkage analysis and direct sequencing were an indicator of the long QT1 gene in our family. Reverse transcription-polymerase chain reaction analysis demonstrated abnormal transcripts in lymphocytes from silent gene carriers. The functional profile of mutated protein isoforms was investigated using the patch–clamp technique. Dynamic analysis of ventricular depolarization was conducted using Holter recordings in patients, and in sex- and age-matched controls. Circadian variations of the QTc interval and the QT/RR relationship were assessed. Sensitivity, specificity, and predictive values were evaluated for proposed clinical criteria. We found that dynamic analysis of the QT interval permitted individual diagnosis in mutation carriers even when the QTc interval was normal (adult males). Conclusion Dynamic analysis of the QT interval is of diagnostic value in the long QT1 syndrome in patients with a normal phenotype. Clinical implications include improvement in screening and patient management.
Published: 2001

50. L’apport du communalisme à la problématique État/Révolution, dans l’œuvre d’Arthur Arnould, socialiste révolutionnaire

Author: Pierre Boisseau
Published: 2000
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