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1. Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting

Author: AL Soilly, C Robert-Viard, C Besse, AL Bruel, B Gerard, A Boland, A Piton, Y Duffourd, J Muller, C Poë, T Jouan, S El Doueiri, L Faivre, D Bacq-Daian, B Isidor, D Genevieve, S Odent, N Philip, M Doco-Fenzy, D Lacombe, ML Asensio, JF Deleuze, C Binquet, DISSEQ Investigators Group, C Thauvin-Robinet, and C Lejeune
Subjects: Intellectual disability, Exome sequencing, Micro-costing, Cost analysis, Public aspects of medicine, RA1-1270
Abstract: Abstract Background With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers. Methods A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed. Results The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID. Conclusion This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES. Trial registration ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.
Published: 2023
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2. Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in <scp>PI3K‐AKT‐mTOR</scp> signaling pathway

Author: Christophe Philippe, Paul Kuentz, Yannis Duffourd, Laurent Guibaud, Pierre Vabres, N. Bourgon, C. Thauvin-Robinet, Virginie Carmignac, Laurence Faivre, and Arthur Sorlin
Subjects: Hemimegalencephaly, Pathology, medicine.medical_specialty, Genetic counseling, Prenatal diagnosis, Germline, AKT3, Phosphatidylinositol 3-Kinases, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Megalencephaly, PI3K/AKT/mTOR pathway, Retrospective Studies, Fetus, Radiological and Ultrasound Technology, business.industry, TOR Serine-Threonine Kinases, Obstetrics and Gynecology, General Medicine, medicine.disease, Reproductive Medicine, Mutation, business, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway.We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid.During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K-AKT-mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA-related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K-AKT-mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Published: 2022

3. Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

Author: Martin Chevarin, Sophie Nambot, Sebastien Moutton, Mirna Assoum, C. Thauvin-Robinet, Quéré, Charlotte Poe, Them Ftm, Ange-Line Bruel, Nolwenn Jean-Marçais, Daphné Lehalle, Nada Houcinat, Yannis Duffourd, Thibaud Jouan, Patrick Callier, Antonio Vitobello, Laurence Faivre, Christophe Philippe, Julien Thevenon, and Tisserand E
Subjects: Male, Candidate gene, medicine.medical_specialty, Adolescent, Sequence analysis, Genomics, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genetics (clinical), Exome sequencing, 0303 health sciences, business.industry, Research, 030305 genetics & heredity, Computational Biology, Sequence Analysis, DNA, medicine.disease, Molecular Diagnostic Techniques, Child, Preschool, Cohort, Medical genetics, Female, business
Abstract: In clinical exome sequencing (cES), the American College of Medical Genetics and Genomics recommends limiting variant interpretation to established human-disease genes. The diagnostic yield of cES in intellectual disability and/or multiple congenital anomalies (ID/MCA) is currently about 30%. Though the results may seem acceptable for rare diseases, they mean that 70% of affected individuals remain genetically undiagnosed. Further analysis extended to all mutated genes in a research environment is a valuable strategy for improving diagnostic yields. This study presents the results of systematic research reanalysis of negative cES in a cohort of 313 individuals with ID/MCA. We identified 17 new genes not related to human disease, implicated 22 non-OMIM disease-causing genes recently or previously rarely related to disease, and described 1 new phenotype associated with a known gene. Twenty-six candidate genes were identified and are waiting for future recurrence. Overall, we diagnose 15% of the individuals with initial negative cES, increasing the diagnostic yield from 30% to more than 40% (or 46% if strong candidate genes are considered). This study demonstrates the power of such extended research reanalysis to increase scientific knowledge of rare diseases. These novel findings can then be applied in the field of diagnostics.
Published: 2019

4. Diagnostic criteria in Pai syndrome: results of a case series and a literature review

Author: Anne Morice, Cecilia Neiva, Arnaud Picard, E. Galliani, Natacha Kadlub, Jeanne Amiel, M. Rachwalski, Marie-Paule Vazquez, C. Thauvin-Robinet, Service de chirurgie plastique et maxillofaciale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie pédiatrique [CHU Necker], Université Sorbonne Paris Cité (USPC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and CCSD, Accord Elsevier
Subjects: Male, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Frontonasal dysplasia, 0302 clinical medicine, Midline cleft lip, Child, 10. No inequality, Corpus Callosum Dysgenesis, Lipoma, Magnetic Resonance Imaging, Coloboma, Phenotype, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Oral Surgery, medicine.medical_specialty, Adolescent, Cleft Lip, PAI SYNDROME, Pericallosal lipoma, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Skin Diseases, Diagnosis, Differential, Young Adult, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Nasal Polyps, Midline facial cleft, otorhinolaryngologic diseases, medicine, Skin tag, Humans, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Alveolar process, Infant, Newborn, Infant, 030206 dentistry, medicine.disease, Dermatology, stomatognathic diseases, Pai syndrome, Otorhinolaryngology, Clinical diagnosis, Surgery, Agenesis of Corpus Callosum, business
Abstract: IF 2.164 (2017); International audience; Pai syndrome was originally described as the association of a midline cleft lip, midline facial polyps, and lipoma of the central nervous system. However, only a few patients present with the full triad, and most exhibit a wide spectrum of phenotypic variability. The aim of this study was to phenotypically delineate Pai syndrome and to propose new criteria to facilitate a clinical diagnosis in the future. The study cohort consisted of seven case patients and an additional 60 cases diagnosed with Pai syndrome identified in a literature review. Only 23 of 67 patients presented the full triad as historically described by Pai et al. (1987). A congenital facial midline skin mass was always encountered, particularly affecting the nasal structures (60/67). A midline facial cleft was reported in 45 of 67 patients and a pericallosal lipoma in 42 of 67 patients. The proposed definition of Pai syndrome is the association of (1) a congenital nasal and/or mediofrontal skin mass and/or a mid-anterior alveolar process polyp as a mandatory criterion, and at least one of the following criteria: (2) midline cleft lip and/or midline alveolar cleft, and/or (3) a pericallosal lipoma or interhemispheric lipoma in the case of corpus callosum dysgenesis.
Published: 2019

5. Expanding the clinical spectrum of mosaic BRAF skin phenotypes

Author: Lisa Weibel, Jean-Baptiste Rivière, Christophe Philippe, Virginie Carmignac, Paul Kuentz, Arthur Sorlin, Sylvie Fraitag, Laurence Faivre, C. Thauvin-Robinet, Pierre Vabres, Yannis Duffourd, Annabel Maruani, Jeanne Amiel, Olivia Boccara, Martin Theiler, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Référence sur les Maladies Génétiques à Expression Cutanée, Partenaires INRAE, Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpital universitaire de Zurich, CHU Dijon, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: 0301 basic medicine, MAPK/ERK pathway, Proto-Oncogene Proteins B-raf, endocrine system diseases, [SDV]Life Sciences [q-bio], Dermatology, DNA sequencing, Serine, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Threonine, neoplasms, ComputingMilieux_MISCELLANEOUS, Skin, Kinase, business.industry, Melanoma, medicine.disease, Phenotype, digestive system diseases, 3. Good health, 030104 developmental biology, Infectious Diseases, Mutation, Cancer research, business, Syringocystadenoma papilliferum
Abstract: BRAF postzygotic activating mutations have been found in 50% of cases of syringocystadenoma papilliferum (SCAP)1 and in phacomatosis pigmentokeratotica (PPK)2,3 , also possibly caused by HRAS4 mutations. BRAF is a RAS-activating serine/threonine kinase of the MAP kinase pathway, resulting in cell growth and proliferation. BRAF mutations, particularly p.(Val600Glu), are frequently identified in melanoma and other human cancers5 . We report clinical presentations of three patients with postzygotic BRAF mutations in affected skin, identified by next generation sequencing (NGS).
Published: 2021

6. Cerebriform sebaceous nevus: a subtype of organoid nevus due to specific postzygotic FGFR2 mutations

Author: C. Thauvin-Robinet, Virginie Carmignac, Laurence Faivre, Arthur Sorlin, Paul Kuentz, Martin Theiler, Lisa Weibel, Kathrin Neuhaus, S. Christen-Zaech, Christophe Philippe, Pierre Vabres, and Martin Chevarin
Subjects: medicine.medical_specialty, Skin Neoplasms, Cutis gyrata, Dermatology, Epidermal nevus, medicine.disease_cause, Germline, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Nevus, Humans, Pediatric dermatology, Receptor, Fibroblast Growth Factor, Type 2, skin and connective tissue diseases, Acanthosis nigricans, Mutation, integumentary system, business.industry, Organoid Nevus, medicine.disease, Organoids, Infectious Diseases, 030220 oncology & carcinogenesis, business
Abstract: Background Postzygotic mutations in FGFR2 have been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans / rounded and velvety epidermal nevus and in two fetuses with papillomatous pedunculated sebaceous nevus (PPSN). Objectives To determine the clinical and genetic characteristics of children with cerebriform, papillomatous, and pedunculated variants of sebaceous nevi. Methods Infants diagnosed with sebaceous nevi characterized by a cerebriform, papillomatous, and/or pedunculated morphology over a 10-year period (2010 - 2019) at three pediatric dermatology centers in Switzerland and France were included in this case series. Clinical and histological characteristics were assessed. Next generation sequencing was used to assess for FGFR2 mutations. Results All nevi were located on the head, with a rounded or linear shape and a typical cerebriform, sometimes papillomatous and pedunculated, surface. No associated extracutaneous anomalies were found. Nevi harbored postzygotic mutations in the transmembrane domain of FGFR2 in 6/8 children (75%), either the known specific p.(Cys382Arg) mutation in 5 cases, or a novel mutation, p.(Val395Asp), in one. Conclusions We found an exquisite genotype-phenotype correlation in these rare nevi, with specific postzygotic mutations in the transmembrane domain of FGFR2. As not all lesions were truly papillomatous and pedunculated, the term cerebriform sebaceous nevus (CSN) appears more suitable than PPSN to describe this entity. The cerebriform pattern of CSN is reminiscent of cutis gyrata, as seen in Beare-Stevenson syndrome, which is caused by closely related germline FGFR2 mutations. While clinically impressive, CSN seem to carry a good prognosis and a low risk for extracutaneous associations.
Published: 2021

7. Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients

Author: M.A. Collonge-Rame, N. Meunier-Beillard, Charles Coutant, C. Populaire, E. Cosset, A. Damette, V. Derangère, C. Thauvin-Robinet, C. Sawka, R. Boidot, C. Loustalot, Catherine Lejeune, Laurence Faivre, G. Bertolone, Matthieu P. Robert, V. Goussot, A. Lançon, Sophie Nambot, J. Albuisson, François Ghiringhelli, and A. Baurand
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Patients, Context (language use), 030105 genetics & heredity, 03 medical and health sciences, Neoplasms, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Testing, CHEK2, Genetics (clinical), Genetic testing, Aged, Incidental Findings, medicine.diagnostic_test, business.industry, Cancer, Regret, General Medicine, Middle Aged, medicine.disease, 030104 developmental biology, Attitude, Family medicine, Anxiety, Female, medicine.symptom, Return of results, business
Abstract: With next generation sequencing, physicians are faced with more complex and uncertain data, particularly incidental findings (IF). Guidelines for the return of IF have been published by learned societies. However, little is known about how patients are affected by these results in a context of oncogenetic testing. Over 4 years, 2500 patients with an indication for genetic testing underwent a gene cancer panel. If an IF was detected, patients were contacted by a physician/genetic counsellor and invited to take part in a semi-structured interview to assess their understanding of the result, the change in medical care, the psychological impact, and the transmission of results to the family. Fourteen patients (0.56%) were delivered an IF in a cancer predisposition gene (RAD51C, PMS2, SDHC, RET, BRCA2, CHEK2, CDKN2A, CDH1, SUFU). Two patients did not collect the results and another two died before the return of results. Within the 10 patients recontacted, most of them reported surprise at the delivery of IF, but not anxiety. The majority felt they had chosen to obtain the result and enough information to understand it. They all initiated the recommended follow-up and did not regret the procedure. Information regarding the IF was transmitted to their offspring but siblings or second-degree relatives were not consistently informed. No major adverse psychological events were found in our experience. IF will be inherent to the development of sequencing, even for restricted gene panels, so it is important to increase our knowledge on the impact of such results in different contexts.
Published: 2020

8. Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data

Author: C. Thauvin-Robinet, Nada Houcinat, Daphné Lehalle, A Vital, Laurence Faivre, Agnès Rötig, Jaak Jaeken, Fan Xia, Matthew N. Bainbridge, Marlène Rio, Sophie Nambot, Jean-Baptiste Rivière, Paul Kuentz, Julien Thevenon, D Gavrilov, Cyril Goizet, Ange-Line Bruel, Fanny Mochel, N Niu, Arthur L. Beaudet, Yannis Duffourd, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and FHU TRANSLAD (CHU de Dijon)
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Candidate gene, Adolescent, data sharing, Mitochondrial disease, Compound heterozygosity, Bioinformatics, Young Adult, 03 medical and health sciences, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Exome Sequencing, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Oxidoreductases Acting on Sulfur Group Donors, whole-exome sequencing, Child, Exome, Cytochrome Reductases, Genetics (clinical), Exome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, GFER, Disease gene identification, medicine.disease, Pedigree, 3. Good health, 030104 developmental biology, mitochondrial condition, Mutation, Congenital cataracts, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business
Abstract: Background Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community. Materials and methods Whole exome sequencing was performed as part of a "diagnostic odyssey" for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER. Results Thanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease. Conclusion This report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra-rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.
Published: 2017

9. Xq28 duplication includingMECP2in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Author: Sophie Rondeau, Charles Coutton, Pierre-Simon Jouk, Lydie Burglen, Alice Goldenberg, Bérénice Doray, Nathalie Marle, Séverine Drunat, Pascal Chambon, P. Callier, Thierry Bienvenu, F. Devillard, M.-L. Moutard, Danielle Martinet, Bernard Aral, Pascale Saugier-Veber, Nathalie Perreton, Marie-Claude Addor, Marguerite Miguet, Martine Doco-Fenzy, N. Le Meur, Anne-Marie Guerrot, J.-L. Alessandri, C. Thauvin-Robinet, R. Touraine, Anne-Claude Tabet, Anne-Laure Mosca-Boidron, S. El Chehadeh, D. Devys, Sébastien Lebon, Alexandra Afenjar, Sandra Chantot-Bastaraud, Laurence Faivre, Emilie Landais, Cathy Philippe, Klaus Dieterich, Valérie Kremer, Julien Thevenon, Véronique Satre, V. des Portes, Francine Mugneret, Willie Reardon, and Fabienne Prieur
Subjects: 0301 basic medicine, Genetics, Pediatrics, medicine.medical_specialty, Genetic counseling, MECP2 duplication syndrome, 030105 genetics & heredity, Biology, medicine.disease, X-inactivation, 3. Good health, Xq28, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, medicine, Asymptomatic carrier, Skewed X-inactivation, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
Published: 2017

10. Unexpected diagnosis of a SHH nonsense variant causing a variable phenotype ranging from familial coloboma and Intellectual disability to isolated microcephaly

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

11. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Author: Laurent Guibaud, Kristin Lindstrom, F. Tran Mau-Them, Alice Masurel, John M. Graham, Yannis Duffourd, Renske Oegema, A. A. Sharkov, Markus Zweier, M. J. van den Boogaard, Thibaud Jouan, Ekaterina R. Lozier, Agnes Chen, M. T. Cho, Sergey Korostelev, Laurence Faivre, Henry J. Lin, F. A. Konovalov, Anaïs Begemann, Patricia I. Dickson, Jennifer Friedman, K.L.I. van Gassen, Boris Keren, Laurence Duplomb, C. Thauvin-Robinet, Moin Vera, Isabelle Marey, Margaret G. Au, Christophe Philippe, Thomas Schmitt-Mechelke, Floor E. Jansen, B. Urteaga, Caroline Nava, Stan F. Nelson, Julian A. Martinez-Agosto, Anita Rauch, Fanny Mochel, and Antonio Vitobello
Subjects: 0301 basic medicine, Adult, Central Nervous System, Male, Heterozygote, Adolescent, data sharing, 030105 genetics & heredity, Biology, developmental epileptic encephalopathies, 03 medical and health sciences, Epilepsy, Young Adult, Neurodevelopmental disorder, Seizures, medicine, Transcriptional regulation, Humans, Genetics(clinical), Child, Gene, Genetics (clinical), Exome sequencing, Genetics, Genetic heterogeneity, Neurodegeneration, High-Throughput Nucleotide Sequencing, Nuclear Proteins, Electroencephalography, Middle Aged, medicine.disease, 030104 developmental biology, Phenotype, Neurodevelopmental Disorders, Mutation, IRF2BPL, Female, Carrier Proteins, exome sequencing, Interferon regulatory factors
Abstract: Purpose: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. Methods: We combined ES analysis and international data sharing. Results: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2–binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. Conclusions: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.
Published: 2019

12. Les modifications de pratique clinique liées à l’arrivée du séquençage haut débit dans le diagnostic génétique des maladies du développement

Author: L, Demougeot, F, Houdayer, A, Pélissier, F, Mohrez, J, Thevenon, Y, Duffourd, S, Nambot, E, Gautier, C, Binquet, M, Rossi, D, Sanlaville, S, Béjean, C, Peyron, C, Thauvin-Robinet, L, Faivre, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Laboratoire d'Economie et de Gestion (LEG), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire d'Economie et de Gestion ( LEG ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique des Anomalies du Développement ( GAD ), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB )
Subjects: Male, High-throughput sequencing, Adolescent, Developmental Disabilities, Genetics, Medical, High-Throughput Nucleotide Sequencing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Health Care Surveys, Diagnosis, Genomic medicine, Developmental abnormalities, Genetics, Humans, Female, France, Practice Patterns, Physicians', Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics
Abstract: IF 0.372; International audience; IntroductionThe arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses.MethodsGeneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken.ResultsOf those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures.DiscussionThe survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort?ConclusionIt is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine.
Published: 2018

13. INTU -related oral-facial-digital syndrome type VI: a confirmatory report

Author: A. Favre, Laurence Perrin, H. Lucron, Yline Capri, Yoann Vial, A. Defo, Anne-Claude Tabet, C. Thauvin-Robinet, Alain Verloes, Sandrine Passemard, N. Elenga, Laurence Faivre, Ange-Line Bruel, Jonathan I. Levy, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Ciliary basal body, Compound heterozygosity, Ciliopathies, 03 medical and health sciences, Intraflagellar transport, CPLANE, Genetics, medicine, Inheritance Patterns, Hamartoma, Humans, INTU, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), business.industry, Infant, Newborn, Infant, Membrane Proteins, Orofaciodigital Syndromes, medicine.disease, Phenotype, Magnetic Resonance Imaging, Cytoskeletal Proteins, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NGS, oral-facial-digital syndrome, business, SNP array
Abstract: Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD syndromes are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD syndromes have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign. Whole-exome sequencing and SNP array identified compound heterozygous variants in the INTU gene, which encodes a protein involved in the positioning of the ciliary basal body. INTU is a subunit of the CPLANE multiprotein complex essential for the assembly of IFT-A particles and intraflagellar transport. This report of a second patient with INTU-related OFD syndrome and the further delineation of its neuroimaging and skeletal phenotype now allow INTU-related OFD syndromes to be classified within the OFD syndrome type VI group. Patients display a phenotype similar to that of mice with a hypomorphic mutation of Intu, but with the addition of a heart defect.
Published: 2018

14. Clinical reappraisal of SHORT syndrome withPIK3R1mutations: toward recommendation for molecular testing and management

Author: David A. Dyment, Judith St-Onge, A. Albanese, Sylvie Manouvrier, S. Garcia, Jean-Baptiste Rivière, Corinne Vigouroux, Delphine Héron, Sahar Mansour, Cynthia J. Curry, Paul Kuentz, D. Delesalle, Leah Slattery, B.L. Luyer, Laurence Faivre, C. Thauvin-Robinet, T. Claudi, Sylvie Odent, Grace Yoon, Frédéric Huet, Jonathan A. Bernstein, S. Mo, Susan M. White, M.-L. Nunes, C. Fagour, Pierre Bitoun, Magali Avila, Sara L. Sawyer, A.M. Innes, Ute Moog, A.A. Lopez, Pål R. Njølstad, Jeanne Amiel, M. Laville, Y. Reznik, Olivier Lascols, Dominique Martin, Martine Le Merrer, Julien Thevenon, Brian Hy Chung, Michèle Mathieu-Dramard, Jørn V. Sagen, Rebekah Jobling, Christine Binquet, and Rainer König
Subjects: 0301 basic medicine, medicine.medical_specialty, Pediatrics, Teething, business.industry, Intrauterine growth restriction, medicine.disease, Short stature, 3. Good health, 03 medical and health sciences, Inguinal hernia, 030104 developmental biology, Endocrinology, SHORT syndrome, Internal medicine, Speech delay, Genetics, Etiology, medicine, medicine.symptom, business, Lipoatrophy, Genetics (clinical)
Abstract: SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR)
Published: 2015

15. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Author: C. Thauvin-Robinet, S. El Chehadeh, Irina Giurgea, Aurélie Bourchany, Frédéric Huet, Stanislas Lyonnet, P.O. Lafontaine, Alice Masurel-Paulet, Dominique Bremond-Gignac, Alice Goldenberg, J. Massy, Laurence Faivre, C. Paillot, Julien Thevenon, D. Thouvenin, Gilles Morin, Alain Bron, Catherine Creuzot-Garcher, Alice Duncombe, and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
Subjects: Male, medicine.medical_specialty, Adolescent, genetic structures, Mowat–Wilson syndrome, Retinal Pigment Epithelium, Biology, Eye, Cataract, chemistry.chemical_compound, Atrophy, Intellectual Disability, Ophthalmology, Genetics, medicine, Humans, Hirschsprung Disease, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Iris (anatomy), Hyphema, Genetics (clinical), Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Retina, Facies, Optic Nerve, Retinal, Anatomy, medicine.disease, eye diseases, Coloboma, Repressor Proteins, medicine.anatomical_structure, chemistry, Child, Preschool, Lens (anatomy), Mutation, Microcephaly, Optic nerve, Female, sense organs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.
Published: 2015

16. Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A

Author: C. Thauvin-Robinet, Hery G, Nicholas Katsanis, Aurélie Fabre, Ecochard-Dugelay E, De Leusse C, Y. Rimet, Ange-Line Bruel, Delarue A, P. Gauchez, Xavier Stéphenne, Patrice Bourgeois, R. Maudinas, Ludmila Francescatto, Céline Brochier-Armanet, Yannis Duffourd, Arnaud Blanchard, Marinier E, Laurence Faivre, Olivier Goulet, Perciliz L. Tan, Caroline Lacoste, J. Sarles, Jean-Pierre Hugot, Clothilde Esteve, K. Mazodier, Sabine Sigaudy, Emmanuel Gonzales, Aurélie Bourchany, Nicolas Lévy, C. Guettier-Bouttier, Catherine Badens, Frédéric Huet, Jean-Baptiste Rivière, Julien Thevenon, Bertrand Roquelaure, and Mina Komuta
Subjects: Candidate gene, Cholestasis, In vivo, Concomitant, Myosin, Immunology, medicine, Cancer research, Biology, medicine.disease, Gene, Loss function, Exome sequencing
Abstract: Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
Published: 2017
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17. Search forReCQL4mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Author: Nadège Gigot, Valeria Capra, Annick Toutain, Alice Goldenberg, Geneviève Pierquin, Nicole Philip, Odile Boute, S. Gauthier, Mariam Tajir, Yves Sznajer, Muriel Holder-Espinasse, Loreto Martorell, Laurence Faivre, J. Piard, Jean-Benoît Courcet, Christine Francannet, Cédric Baumann, Philippe Parent, Valérie Cormier-Daire, Michael Wright, N. Didonato, Marie-Pierre Cordier, David Geneviève, Didier Bessis, Ana Berta Sousa, Laurent Pasquier, Angela F. Brady, F. Boralevi, Siham Chafai Elalaoui, André Mégarbané, Bernard Aral, Edward Blair, Christine Bodemer, Eve Puzenat, B. Demeer, M. Tardieu, Corinne Collet, V. Barlogis, C. Thauvin-Robinet, Marlène Rio, Christine Coubes, Pierre Vabres, Geneviève Baujat, J. Franques, Patrick Callier, Jean-Baptiste Rivière, María Antonia González-Enseñat, Julien Thevenon, Olga Domnica Moldovan, and A. Rodríguez
Subjects: Genetics, medicine.medical_specialty, business.industry, Poikiloderma, Consanguinity, Baller–Gerold syndrome, medicine.disease, Dermatology, 3. Good health, Hereditary sclerosing poikiloderma, Genotype, medicine, business, Rothmund–Thomson syndrome, Genetics (clinical), Comparative genomic hybridization, Porokeratosis
Abstract: Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.
Published: 2014

18. Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature

Author: Elodie Gautier, David Geneviève, V. Goussot, A.S. Lapointe, Aurore Pélissier, Marc Bardou, C. Sawka, C. Thauvin-Robinet, Laurence Faivre, François Ghiringhelli, Elodie Cretin, F. Tran Mau-Them, Damien Sanlaville, G. Bertolone, R. Boidot, Catherine Lejeune, Christine Binquet, Julian Delanne, Antonio Vitobello, Ange-Line Bruel, A. Baurand, Yannis Duffourd, Maxime Luu, Christine Peyron, Christine Juif, Aline Chassagne, Laurent Demougeot, Christophe Philippe, Sophie Nambot, Olivier Putois, Françoise Houdayer, Julien Thevenon, L. Joly, P. Pujol, C. Vernin, 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), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, INSERM Centre Innovation Technologique 808 (INSERM CIT 808), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Subjectivité, lien social et modernité (SuLiSoM), Université de Strasbourg (UNISTRA), Laboratoire d'Economie de Dijon [Dijon] (LEDi), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Plateau technique de Biologie [CHU de Dijon], Université Bourgogne Franche-Comté [COMUE] (UBFC), 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), 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, Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CCSD, Accord Elsevier, Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), and UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon)
Subjects: 0301 basic medicine, medicine.medical_specialty, Patients, Genetic Counseling, Disclosure, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030105 genetics & heredity, Choice Behavior, 03 medical and health sciences, Secondary findings, Stakeholder Participation, Informed consent, Multidisciplinary approach, Exome Sequencing, Genetics, medicine, Humans, Genetic Testing, Medical prescription, Exome, Genetics (clinical), Literature review, Incidental Findings, Opinion based studies, Modalities, Stakeholder, Subject (documents), General Medicine, 3. Good health, Test (assessment), 030104 developmental biology, Attitude, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Family medicine, Psychology, Actionability
Abstract: IF 2.004 (2017); International audience; With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice» is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.
Published: 2019

19. Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

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

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

Author: M, Lefebvre, D, Sanlaville, N, Marle, C, Thauvin-Robinet, E, Gautier, S E, Chehadeh, A-L, Mosca-Boidron, J, Thevenon, P, Edery, M-P, Alex-Cordier, M, Till, S, Lyonnet, V, Cormier-Daire, J, Amiel, A, Philippe, S, Romana, V, Malan, A, Afenjar, S, Marlin, S, Chantot-Bastaraud, P, Bitoun, B, Heron, E, Piparas, F, Morice-Picard, S, Moutton, N, Chassaing, A, Vigouroux-Castera, J, Lespinasse, S, Manouvrier-Hanu, O, Boute-Benejean, C, Vincent-Delorme, F, Petit, N L, Meur, M, Marti-Dramard, A-M, Guerrot, A, Goldenberg, S, Redon, C, Ferrec, S, Odent, C L, Caignec, S, Mercier, B, Gilbert-Dussardier, A, Toutain, S, Arpin, S, Blesson, I, Mortemousque, E, Schaefer, D, Martin, N, Philip, S, Sigaudy, T, Busa, C, Missirian, F, Giuliano, H K, Benailly, P K V, Kien, B, Leheup, C, Benneteau, L, Lambert, R, Caumes, P, Kuentz, I, François, D, Heron, B, Keren, E, Cretin, P, Callier, S, Julia, L, Faivre, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Université de Bourgogne (UB), Service de Génétique, Hospices Civils de Lyon (HCL), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM EMI0210 (EMI0210), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Hôpital Jean Verdier [AP-HP], Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Le Mans (CH Le Mans), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital l'Archet, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Dijon, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical Investigation Centre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Pain & Palliative Care Department, Université de Franche-Comté (UFC), Logiques de l'Agir ( UR 2274) (LdA), The authors thanks the Regional Council of Burgundy for their support., Jonchère, Laurent, Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne ( UB ), Hospices Civils de Lyon ( HCL ), Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Institut National de la Santé et de la Recherche Médicale, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSERM EMI0210 ( EMI0210 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Service de neurologie pédiatriques, Service de neuropédiatrie [Trousseau]-Centre de Référence des Maladies Lysosomales, Hôpital Jean Verdier, Maladies Rares - Génétique et Métabolisme ( MRGM ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Toulouse, Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Hôpital Bretonneau-CHRU Tours, CHU Le MAns, Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de neuropédiatrie [Trousseau], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Franche-Comté ( UFC ), Université de Franche-Comté ( UFC ), Logiques de l'Agir - UFC ( LdA ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Logiques de l'Agir ( EA 2274) ( LdA ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Logiques de l'Agir ( EA 2274) (LdA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Comparative Genomic Hybridization, Physician-Patient Relations, [SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Genetic Diseases, Inborn, Genes, Recessive, Genetic Counseling, Genetic Diseases, X-Linked, Disclosure, [SDV.GEN] Life Sciences [q-bio]/Genetics, Microarray Analysis, [SDV] Life Sciences [q-bio], incidental findings, aCGH, Surveys and Questionnaires, Humans, Female, ethical issues, pre-test information, France, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Genes, Dominant, Retrospective Studies
Abstract: International audience; Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
Published: 2016

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

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

22. Mosaic-activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus

Author: C. Thauvin-Robinet, N. Joye, Nathalie Marle, Yannis Duffourd, Jean-Marie Jouannic, Julien Thevenon, Laurence Faivre, Jean-Baptiste Rivière, Ferdinand Dhombres, Judith St-Onge, Pierre Vabres, Sylvie Fraitag, A. Picard, Marie Gonzales, Paul Kuentz, Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique et embryologie médicales [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), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Université Paris 13 (UP13)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Service de chirurgie plastique et maxillofaciale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire de cytogénétique (CHU de Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de Dermatologie (CHU de Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé ( LIMICS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris 13 ( UP13 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris Descartes - Paris 5 ( UPD5 ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Université Paris 13 ( UP13 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de chirurgie plastique et maxillofaciale [CHU Necker-Enfants-Malades], and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, papillomatous, Dermatology, Biology, medicine.disease_cause, Deep sequencing, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, PPSN, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Nevus, Missense mutation, naevus, HRAS, Fetus, Mutation, integumentary system, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Schimmelpenning syndrome, Scalp, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole-exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34[middle dot]6% of reads which was absent in the parents' blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS-related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.
Published: 2016

23. Incidence des troubles neuropsychiatriques chez les patients adultes atteints de phénylcétonurie : résultats de la cohorte ECOPHEN

Author: S. Charrière, C. Douillard, C. Thauvin-Robinet, Jean-Baptiste Arnoux, François Maillot, F. Feillet, H. Levesque, Christian Lavigne, S. Odent, A. Caille, L. Astudillo, and A. Fouilhoux
Subjects: 03 medical and health sciences, 0302 clinical medicine, Gastroenterology, Internal Medicine, 030209 endocrinology & metabolism, 030217 neurology & neurosurgery
Abstract: Introduction La phenylcetonurie (PCU) est une maladie metabolique rare qui est depistee chez tous les nouveau-nes en France. Les enfants atteints sont traites pendant l’enfance par un regime controle en phenylalanine, jusqu’a un âge variable. L’evolution de la maladie a l’âge adulte est partiellement decrite et certains resultats montrent que le pronostic de ces patients n’est pas optimal [1] . L’objectif de notre etude etait de decrire l’incidence des complications neuropsychiatriques de ces patients adultes atteints de PCU. Patients et methodes Le projet ECOPHEN est une etude de cohorte multicentrique prospective de patients adultes atteints de PCU. Tous les patients ont ete diagnostiques suite au depistage neonatal. Les resultats de la visite d’inclusion sont presentes et exprimes en moyenne ± ecart-type. Resultats Cent quatre-vingt-sept patients ont ete inclus (127 femmes, 60 hommes, âge 27,6 ± 6,3 ans). Le nombre de patients avec PCU classique, PCU atypique et hyperphenylalaninemie persistante (HMP) etait respectivement de 152, 26 et 9. Cinquante-trois pour cent des patients etaient traites par un regime controle en phenylalanine. Au total, 20 patients (10,7 %) ont eu des troubles neurologiques, uniquement dans le groupe PCU classique (cephalees, tremblements, troubles de l’equilibre ou troubles visuels…). Quarante-huit patients (25,7 %) ont developpe des troubles psychiatriques varies (depression anxiete, troubles du comportement alimentaire…), et ce dans les 3 types de PCU : 40 patients (26,3 %) avec PCU classique vs 6 (23,1 %) avec PCU atypique, vs 2 (22,2 %) avec HMP (NS). Discussion Cette etude a permis d’inclure un grand nombre de patients adultes atteints de PCU, majoritairement de type PCU classique. La population feminine est tres majoritairement representee, en raison des enjeux qui concernent la grossesse PCU. Dans cette etude, l’incidence des troubles neurologiques est faible mais non negligeable, avec des manifestations plus ou moins severes, dont certaines sont reversibles apres une reprise de traitement de la PCU. L’incidence des troubles psychologiques/psychiatriques parait elevee, et ce dans les 3 groupes de patients. L’absence de groupe temoin ne permet pas de savoir si cette incidence est significativement plus elevee par rapport a des sujets sains. Conclusion L’incidence des troubles neuropsychiatriques n’est pas negligeable dans la PCU de l’adulte. Ces resultats suggerent de maintenir un regime controle en phenylalanine a long terme [2] . Le suivi des patients atteints de PCU doit inclure un depistage systematique des troubles neuropsychiatriques.
Published: 2017

24. What can we learn from old microdeletion syndromes using array-CGH screening?

Author: Nathalie Marle, Muriel Holder-Espinasse, C. Ragon, P. Callier, Anne Dieux-Coeslier, Anne-Laure Mosca-Boidron, Philippe Jonveaux, Joris Andrieux, Catherine Vincent-Delorme, Muriel Payet, Brigitte Benzacken, Francine Mugneret, E Questiaux, Ghislaine Plessis, Eva Pipiras, C. Thauvin-Robinet, Alice Masurel-Paulet, Sonia Bouquillon, Andrée Delahaye, C Bonnet, Sylvie Manouvrier-Hanu, M Berri, and Laurence Faivre
Subjects: Adult, Adolescent, Genotype, Chromosomes, Human, Pair 22, Karyotype, Biology, Bioinformatics, Intellectual Disability, Variable phenotype, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Comparative Genomic Hybridization, medicine.disease, Phenotype, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 7, Modifier Genes, Comparative genomic hybridization
Abstract: Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.
Published: 2011

25. A prenatal case of inverted duplication with terminal deletion of 5p not including the cat-like cry critical region

Author: C. Thauvin-Robinet, Nathalie Marle, Thierry Rousseau, Francine Mugneret, Patrick Callier, Alice Masurel-Paulet, A.L. Mosca, Nicole Laurent, S. Couvreur, Laurence Faivre, Muriel Payet, Paul Sagot, and H. Guy
Subjects: Adult, Genetics, Inverted duplication, Biology, Chromosome Banding, Terminal (electronics), Pregnancy, Aborted Fetus, Chromosome Duplication, Chromosome Inversion, Cat-like cry, Amniocentesis, Chromosomes, Human, Pair 5, Humans, Abnormalities, Multiple, Female, Chromosome Deletion, Abortion, Eugenic, In Situ Hybridization, Fluorescence, Genetics (clinical)
Published: 2011

26. Variations de prévalence de la trisomie 21 en population française entre 1978 et 2005

Author: Jean-Bernard Gouyon, Cyril Ferdynus, T. Rousseau, E. Amar, Paul Sagot, and C. Thauvin-Robinet
Subjects: Gynecology, medicine.medical_specialty, Reproductive Medicine, business.industry, medicine, Obstetrics and Gynecology, General Medicine, business
Abstract: Resume Objectifs Evaluer l’impact de l’augmentation de l’âge des meres et du diagnostic prenatal sur la prevalence de la trisomie 21 dans un echantillon de la population francaise. Patients et methodes Les donnees sur la trisomie 21 ont ete obtenues a partir du registre de malformations congenitales REMERA entre 1978 et 2005. La population surveillee correspond a environ 10 % des naissances francaises. Nous avons etudie la prevalence totale, la prevalence des naissances vivantes ainsi que la prevalence des interruptions de grossesse apres diagnostic prenatal positif. Resultats L’âge moyen des meres a augmente passant de 26 a 30 ans sur la duree de l’etude. La prevalence totale de la trisomie 21 est passee de 14/10 000 en 1978 a 23/10 000 naissances vivantes en 2005. L’augmentation progressive du nombre d’interruption de grossesse apres diagnostic prenatal atteint 78 % des cas en 2005. La prevalence a la naissance a diminue, passant de 14/10 000 en 1978 a 5,1/10 000 en 2005. Conclusion Il est important de continuer la surveillance epidemiologique de la trisomie 21 en France, notamment du fait des changements dans les caracteristiques demographiques de la population mais egalement dans les politiques de depistage prenatal de la trisomie 21.
Published: 2010

27. Impact des variations de distribution de l’âge maternel sur la prévalence attendue à la naissance de la trisomie 21 en France métropolitaine entre 1965 et 2008

Author: Cyril Ferdynus, C. Thauvin-Robinet, T. Rousseau, Paul Sagot, and Jean-Bernard Gouyon
Subjects: Reproductive Medicine, Obstetrics and Gynecology, General Medicine
Abstract: Resume Objectifs Evaluer l’impact des facteurs demographiques tels que l’âge des meres sur la prevalence attendue de la trisomie 21 a la naissance. Patients et methodes Nous avons utilise les donnees demographiques nationales francaises colligees par l’Insee portant sur les naissances vivantes ainsi que sur l’âge des meres. La prevalence attendue a la naissance est calculee a partir d’un modele mathematique de regression logistique largement utilise dans le depistage serique de la trisomie 21 fœtale par le dosage des marqueurs seriques maternels. Resultats Nous presentons des donnees continues de prevalence attendue a la naissance sur une large periode qui s’etend de 1965 a 2008. Durant les trois dernieres decennies, l’âge moyen des meres a augmente de quatre annees, entrainant un doublement de la prevalence attendue de la trisomie 21 a la naissance, passant de 12,1 pour 10 000 naissances vivantes en 1977 a 21,7 pour 10 000 a 2008. Conclusion Il est important de continuer a prendre en compte l’impact des modifications de facteurs demographiques tels que l’âge maternel, notamment dans le cadre de l’evaluation des pratiques et des strategies de depistage de la trisomie 21.
Published: 2010

28. Cytogenetic and array-CGH characterization of a 6q27 deletion in a patient with developmental delay and features of Ehlers-Danlos syndrome

Author: M. Nouchy, A.L. Mosca, C. Thauvin-Robinet, Paul Coucke, A. De Paepe, Francine Mugneret, Laurence Faivre, Nathalie Marle, Dominique Dipanda, Patrick Callier, Frédéric Huet, and Alice Masurel-Paulet
Subjects: Adult, Chromosomes, Artificial, Bacterial, medicine.medical_specialty, Systemic disease, Developmental Disabilities, Gene mapping, Genetics, medicine, Humans, Child, Genetics (clinical), Comparative Genomic Hybridization, business.industry, Infant, Newborn, Cytogenetics, Infant, medicine.disease, Chromosome Banding, Developmental disorder, Ehlers–Danlos syndrome, Child, Preschool, Karyotyping, Chromosomes, Human, Pair 6, Ehlers-Danlos Syndrome, Female, Chromosome Deletion, business
Published: 2010

29. Detection of an interstitial 3q21.1-q21.3 deletion in a child with multiple congenital abnormalities, mental retardation, pancytopenia, and myelodysplasia

Author: Frédéric Huet, C. Thauvin-Robinet, Jean-Raymond Teyssier, J. Guy, Laurence Faivre, D. Assous, Nathalie Marle, Patrick Callier, Alice Masurel-Paulet, Francine Mugneret, P. D'Athis, and A.L. Mosca
Subjects: Genetics, Comparative Genomic Hybridization, Pediatrics, medicine.medical_specialty, business.industry, Cancer, DNA, medicine.disease, Pancytopenia, Chromosome Banding, Developmental disorder, Intellectual Disability, Karyotyping, Myelodysplastic Syndromes, medicine, Humans, Abnormalities, Multiple, Female, Chromosomes, Human, Pair 3, Chromosome Deletion, Child, business, In Situ Hybridization, Fluorescence, Genetics (clinical)
Published: 2009

30. Polymicrogyria in a child with inv dup del(9p) and 22q11.2 microduplication

Author: Nathalie Marle, Nathalie Madinier, Francine Mugneret, S. Ragot, Christine Durand, Laurence Faivre, N. Méjean, Alice Masurel-Paulet, Patrick Callier, Frédéric Huet, G. Couillaud, A.L. Mosca, C. Thauvin-Robinet, and Jean-Raymond Teyssier
Subjects: Chromosomes, Artificial, Bacterial, Candidate gene, Chromosomes, Human, Pair 22, Biology, Polymerase Chain Reaction, Chromosome Painting, Gene duplication, Genetics, Polymicrogyria, medicine, Humans, Child, In Situ Hybridization, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Chromosome Aberrations, Nucleic Acid Hybridization, Chromosome Breakage, Karyotype, Physical Chromosome Mapping, medicine.disease, Malformations of Cortical Development, Karyotyping, Cytogenetic Analysis, dup, Speech delay, Female, Chromosome Deletion, medicine.symptom, Chromosome breakage, Chromosomes, Human, Pair 9, Comparative genomic hybridization
Abstract: Polymicrogyria (PMG) is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12-year-old girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplication/deletion and bacterial artificial chromosomes (BACs)-array also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACs-array in detecting complex rearrangements.
Published: 2009

31. Array-CGH in a series of 30 patients with mental retardation, dysmorphic features, and congenital malformations detected an interstitial 1p22.2-p31.1 deletion in a patient with features overlapping the Goldenhar syndrome

Author: Frédéric Huet, A.L. Mosca, Patrick Callier, C. Thauvin-Robinet, Nathalie Marle, Simon Guiraud, Jean-Raymond Teyssier, Alice Masurel-Paulet, J. Guy, Laurence Faivre, L. Joly, P. D'Athis, and Francine Mugneret
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Developmental Disabilities, Goldenhar syndrome, Biology, Short stature, Goldenhar Syndrome, Intellectual Disability, Genetics, medicine, Humans, Cyst, Child, In Situ Hybridization, Fluorescence, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Cytogenetics, Dysostosis, Karyotype, Middle Aged, medicine.disease, Subtelomere, Chromosomes, Human, Pair 1, Child, Preschool, Karyotyping, Female, Chromosome Deletion, medicine.symptom, Comparative genomic hybridization
Abstract: Genosensor Array 300 (Abbott) is a multiplex platform for array-based comparative genomic hybridization that detects unbalanced genomic aberrations including whole chromosome gains/losses, microdeletions, duplications and unbalanced subtelomeric rearrangements. A series of 30 patients with unexplained mental retardation, dysmorphic features, congenital abnormalities and normal high resolution karyotype and FISH subtelomeric studies were analyzed using Genosensor Array 300 array-CGH. We identified a chromosomal aberration in one patient with an interstitial 1p31.1 deletion. FISH analysis with BACs specific probes of the 1p region confirmed the interstitial 1p22.2-p31.1 deletion. The patient was a 20-year-old man with short stature, facial dysmorphism including asymmetry, scoliosis, severe psychomotor delay and an epibulbar dermoid cyst. The phenotype was compatible with Goldenhar syndrome despite the absence of asymmetric ears. This observation is of interest since it could be a clue in the search for the genes responsible for Goldenhar syndrome. This study demonstrates the utility of the array-CGH technology in detecting interstitial deletions.
Published: 2008

32. Untreated growth hormone deficiency with extremely short stature, bone dysplasia, cleft lip–palate and severe mental retardation in a 26-year-old man with a de novo unbalanced translocation t(1;12)(q24;q24)

Author: Laurence Faivre, Nathalie Marle, Frédéric Huet, A. Danino, Patrick Callier, C. Thauvin-Robinet, Francine Mugneret, G. Malka, S. Falcon-Eicher, M. Le Merrer, Alice Masurel-Paulet, J. Borgnon, and A.L. Mosca
Subjects: Adult, Male, medicine.medical_specialty, Cleft Lip, Chromosomal translocation, Biology, Short stature, Translocation, Genetic, Growth hormone deficiency, Molecular cytogenetics, Intellectual Disability, Internal medicine, Genetics, medicine, Humans, Growth Disorders, In Situ Hybridization, Fluorescence, Genetics (clinical), Bone Diseases, Developmental, Chromosomes, Human, Pair 12, Cytogenetics, Karyotype, General Medicine, medicine.disease, Cleft Palate, Developmental disorder, Endocrinology, Chromosomes, Human, Pair 1, Dysplasia, Growth Hormone, Karyotyping, medicine.symptom
Abstract: We report on a 26-year-old patient presenting with extremely short stature (height 72cm, weight 6.5kg, OFC 42.5cm), facial dysmorphism, cleft lip--palate, severe mental retardation and de novo 1q24.2--q25.2 and 12q24.31 interstitial deletion. He was the only child of non-consanguineous parents and his birth length was 43cm. He had severe feeding difficulties and required enteral nutrition until the age of 3 years. Standard cytogenetic analysis showed an apparently balanced de novo translocation t(1;12)(q24;q24). Endocrine studies at 11 years of age for severe growth retardation revealed multiple pituitary hormone deficiency with severe growth hormone deficiency, but the child was untreated because of associated mental retardation. At 26 years of age, he could not walk or speak and had no signs of puberty. Investigations revealed spondylo-epi-metaphyseal dysplasia with severe osteoporosis, enlarged aorta when compared to the patient's size and apparently normal pituitary development. High resolution karyotype showed a 1q24-q25 deletion, and comparative genomic hybridization studies confirmed the 1q interstitial deletion. FISH studies of both breakpoints using PACs and BACs enabled us to further characterize the 1q interstitial deletion (1q24.2-1q25.2) and also revealed a 12q24.31 interstitial microdeletion. This case is compared with previously reported patients with similar deletions, but the untreated pituitary deficiency could also be responsible in part for the severity of the growth deficiency. This observation is of interest for two reasons. First, these deletions could be a clue in the search for a gene responsible for growth hormone deficiency/midline defects. Second, it shows the importance of molecular cytogenetics in the study of de novo apparently balanced translocation with abnormal phenotype.
Published: 2007

33. Troubles du métabolisme des cobalamines chez l’adulte

Author: Emmanuel Roze and C. Thauvin-Robinet
Subjects: Gynecology, medicine.medical_specialty, B vitamins, Neurology, business.industry, medicine, Thromboembolic disease, Neurology (clinical), Venous disease, business
Abstract: Resume Introduction Les maladies du metabolisme des cobalamines peuvent etre secondaires a une anomalie de l’absorption, du transport ou de la synthese intracellulaire des cobalamines. Ces maladies se revelent habituellement dans les premieres annees de vie par une anomalie hematologique et des difficultes d’alimentation. La maladie debute parfois plus tardivement chez l’adolescent ou l’adulte avec une presentation qui peut etre exclusivement neuropsychiatrique. Etat des connaissances Le tableau le plus evocateur est celui d’une atteinte neurologique subaigue similaire a ce que l’on peut observer dans les carences d’apport en vitamine B 12 ou dans la maladie de Biermer, en particulier une atteinte de type sclerose combinee de la moelle. Dans ce contexte, les indices complementaires pouvant orienter vers ce diagnostic sont : l’existence d’une anemie megaloblastique associee a l’atteinte neurologique ; l’existence d’antecedents de thrombose veineuse ; l’association de troubles neurologiques et de troubles psychiatriques ; l’association d’une atteinte neurologique centrale et peripherique. Les examens diagnostiques determinants sont la chromatographie des acides amines qui montre une hyperhomocystinemie ainsi qu’une hypomethioninemie et la chromatographie des acides organiques urinaires qui peut retrouver une acidurie methylmalonique. Ces anomalies signent l’existence d’un deficit intracellulaire en cobalamines. Le traitement depend du defaut metabolique mais repose constamment sur la supplementation a vie en hydroxocobalamine par voie intramusculaire. Il permet dans la grande majorite des cas une stabilisation ou une recuperation neurologique. Conclusion L’evolution naturelle des maladies du metabolisme des cobalamines est severe et souvent fatale alors qu’il existe un traitement efficace. Nous recommandons d’evoquer ce diagnostic devant toute atteinte neurologique inexpliquee de l’adulte dont le tableau est compatible et de la tester par un simple dosage de l’homocysteine totale plasmatique.
Published: 2007

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

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

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

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

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

Author: M, Avila, D A, Dyment, J V, Sagen, J, St-Onge, U, Moog, B H Y, Chung, S, Mo, S, Mansour, A, Albanese, S, Garcia, D O, Martin, A A, Lopez, T, Claudi, R, König, S M, White, S L, Sawyer, J A, Bernstein, L, Slattery, R K, Jobling, G, Yoon, C J, Curry, M L, Merrer, B L, Luyer, D, Héron, M, Mathieu-Dramard, P, Bitoun, S, Odent, J, Amiel, P, Kuentz, J, Thevenon, M, Laville, Y, Reznik, C, Fagour, M-L, Nunes, D, Delesalle, S, Manouvrier, O, Lascols, F, Huet, C, Binquet, L, Faivre, J-B, Rivière, C, Vigouroux, P R, Njølstad, A M, Innes, C, Thauvin-Robinet, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Children's hospital of Eastern Ontario Research Institute, University of Bergen (UiB), Haukeland University Hospital, Human Genetics Institute, Heidelberg University, Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, St George's Hospital, INGEMM, Instituto de Genética Médica y Molecular, IDIPAZ-Hospital Universitario La Paz, Instituto de Salud Carlos III [Madrid] (ISC), Hospital Central de la Cruz Roja San Jose y Santa Adela, University Hospital Puerta de Hierro, Madrid, Bodø University College, Humangenetik, Universitätsklinikum Frankfurt, University of Frankfurt, University of Melbourne, Victorian Clinical Genetics Services, Stanford University, The Hospital for sick children [Toronto] (SickKids), University of California [San Francisco] (UCSF), University of California, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CH Le Havre, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], CHU Amiens-Picardie, Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Bordeaux [Bordeaux], CH Valenciennes, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Calgary, Financial support was from the Regional Council of Burgundy and the Care4Rare Canada Consortium was funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’sHospital of Eastern Ontario Foundation. DAD is the recipient of a CIHR Clinical Investigator award from the Institute of Genetics. PRN was supported in part by grants from the Research Council of Norway, The University of Bergen, an ERC Advanced Grant, Helse Vest and the KG Jebsen Foundation., SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, University of Bergen (UIB), Instituto de Salud Carlos III (ISC), Stanford University [Stanford], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Service de neuropédiatrie [Trousseau], Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Recherche Clinique, Université Joseph Fourier - Grenoble 1 (UJF)-Centre de Recherche en Nutrition Humaine Rhône - Alpes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, University of Bergen ( UIB ), The University of Hong Kong ( HKU ), Instituto de Salud Carlos III (ISCIII) - Spain RDR - CIBERER, University of California [San Francisco] ( UCSF ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre de Recherche en Nutrition Humaine Rhône - Alpes, Cancers et préventions, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of California [San Francisco] (UC San Francisco), University of California (UC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)
Subjects: short stature, lipoatrophy, intrauterine growth restriction, [ SDV ] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV]Life Sciences [q-bio], Diabetes, PIK3R1 gene, Insulin Resistance, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, SHORT syndrome
Abstract: International audience; SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
Published: 2015

37. OFD1 mutations in males: phenotypic spectrum and ciliary basal body docking impairment

Author: C, Thauvin-Robinet, S, Thomas, M, Sinico, B, Aral, L, Burglen, N, Gigot, H, Dollfus, S, Rossignol, M, Raynaud, C, Philippe, C, Badens, R, Touraine, C, Gomes, B, Franco, E, Lopez, N, Elkhartoufi, L, Faivre, A, Munnich, N, Boddaert, L, Van Maldergem, F, Encha-Razavi, S, Lyonnet, M, Vekemans, E, Escudier, T, Attié-Bitach, C., Thauvin Robinet, S., Thoma, M., Sinico, B., Aral, L., Burglen, N., Gigot, H., Dollfu, S., Rossignol, M., Raynaud, C., Philippe, C., Baden, R., Touraine, C., Gome, Franco, Brunella, E., Lopez, N., Elkhartoufi, L., Faivre, A., Munnich, N., Boddaert, L. V., Maldergem, F., Encha Razavi, S., Lyonnet, M., Vekeman, E., Escudier, and T. Attié B. i. t. a. c., H.
Subjects: Male, Adolescent, Genotype, Infant, Newborn, Proteins, Genetic Diseases, X-Linked, Kidney Diseases, Cystic, Orofaciodigital Syndromes, Basal Bodies, Retina, Young Adult, Phenotype, Cerebellar Diseases, Cerebellum, Child, Preschool, Mutation, Humans, Abnormalities, Multiple, Cilia, Eye Abnormalities, Child
Published: 2013

38. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

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

39. Major feeding difficulties in the first reported case of interstitial 20q11.22-q12 microdeletion and molecular cytogenetic characterization

Author: Patrick Callier, Francine Mugneret, Marc Labenne, Nathalie Marle, P. Gosset, Damien Sanlaville, C. Thauvin-Robinet, Marguerite Prieur, Laurence Faivre, and Frédéric Huet
Subjects: medicine.medical_specialty, Chromosomes, Human, Pair 20, Biology, Feeding and Eating Disorders, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, In Situ Hybridization, Fluorescence, Genetics (clinical), Breakpoint, Cytogenetics, Facies, Infant, Chromosome, Karyotype, Phenotype, Chromosome Banding, Child, Preschool, Karyotyping, Cytogenetic Analysis, Female, Chromosome Deletion, Abnormality, Chromosome 20, Follow-Up Studies, Comparative genomic hybridization
Abstract: We report on a 4-year-old female presenting with intrauterine growth retardation, facial dysmorphic features, major feeding difficulties with severe diarrhea and vomiting, mental retardation with abnormal behavior and hypertonia. Feeding difficulties were the most invalidating features with absent oral intake requiring persistent enteral feeding. Standard cytogenetic studies were normal, but high-resolution chromosome analyses revealed a small de novo interstitial deletion of the long arm of chromosome 20, 46,XX,del(20)(q11.21q12). The deletion was confirmed using metaphase comparative genomic hybridization (CGH) and multicolor high resolution banding (mBAND). The deletion breakpoints were characterized using FISH analyses with YACs, PACs, and BACs clones located in the deleted and adjacent regions. A 6.6-Mb deleted region between markers D20S815 (20q11.22) and D20S435 (20q12) could be delineated. None of the nine previously reported cases with interstitial 20q deletion found in the literature involve the same breakpoints. This report further emphasizes the indication of high-resolution chromosome analyses in children with syndromic mental retardation. The description of additional cases would be useful in order to better characterize the phenotype of patients with proximal interstitial 20q deletion.
Published: 2006

40. Search for genomic imbalances in a cohort of 20 patients with oral-facial-digital syndromes negative for mutations and large rearrangements in the OFD1 gene

Author: C. Thauvin Robinet, P. Callier, O. Zuffardi, M. Payet, B. Aral, N. Gigot, A. Donzel, A. L. Mosca Boidron, A. Masurel Paulet, F. Huet, J. R. Teyssier, F. Mugneret, L. Faivre, FRANCO, BRUNELLA, C., Thauvin Robinet, P., Callier, Franco, Brunella, O., Zuffardi, M., Payet, B., Aral, N., Gigot, A., Donzel, A. L., Mosca Boidron, A., Masurel Paulet, F., Huet, J. R., Teyssier, F., Mugneret, and L., Faivre
Published: 2009

41. Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers

Author: M. Béri, Philippe Jonveaux, S. El Chehadeh, P. Callier, Julien Thevenon, Céline Bonnet, Muriel Payet, Alice Masurel-Paulet, Clémence Ragon, N. Seta, Laurence Faivre, Anne-Laure Mosca-Boidron, C. Thauvin-Robinet, Francine Mugneret, T. Dupré, Laurence Duplomb, and Nathalie Marle
Subjects: Genetics, Microcephaly, education.field_of_study, business.industry, Population, medicine.disease, Bioinformatics, Short stature, Article, Oligosaccharyltransferase complex, Speech delay, Intellectual disability, Gene duplication, medicine, medicine.symptom, business, education, Gene
Abstract: Intellectual disability (ID), which affects around 2–3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients’ fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.
Published: 2014

42. What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

Author: F, Coron, T, Rousseau, G, Jondeau, E, Gautier, C, Binquet, L, Gouya, V, Cusin, S, Odent, Y, Dulac, H, Plauchu, P, Collignon, M-A, Delrue, B, Leheup, L, Joly, F, Huet, J, Thevenon, G, Mace, C, Cassini, C, Thauvin-Robinet, J E, Wolf, N, Hanna, P, Sagot, C, Boileau, L, Faivre, Centre de référence MARFAN, Hôpital Bichat, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Génétique, Hôtel Dieu, Centre Hospitalier de toulon, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Parents, Adolescent, Genetics, Medical, [SDV]Life Sciences [q-bio], Middle Aged, Marfan Syndrome, Young Adult, Prenatal Diagnosis, Surveys and Questionnaires, Humans, Female, France, Preimplantation Diagnosis
Abstract: International audience; Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. Two different questionnaires were produced. Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.
Published: 2012

43. An improved method to extract DNA from 1 ml of uncultured amniotic fluid from patients at less than 16 weeks' gestation

Author: Julien Thevenon, C. Thauvin-Robinet, Anne-Laure Mosca-Boidron, Frédéric Huet, Laurence Faivre, Thierry Rousseau, Patrick Callier, Muriel Payet, Paul Sagot, Clémence Ragon, Serge Aho, Nathalie Marle, Salima El Chehadeh, Caroline Truntzer, and Francine Mugneret
Subjects: Adult, Pathology, medicine.medical_specialty, Amniotic fluid, lcsh:Medicine, Aneuploidy, Prenatal diagnosis, Gestational Age, Biology, Sensitivity and Specificity, Andrology, Cytogenetics, Chromosomal Disorders, Pregnancy, Diagnostic Medicine, Prenatal Diagnosis, medicine, Genetics, Humans, lcsh:Science, Pregnancy Trimesters, Chromosome Aberrations, Clinical Genetics, Comparative Genomic Hybridization, Multidisciplinary, lcsh:R, Gestational age, Obstetrics and Gynecology, Human Genetics, DNA, medicine.disease, Amniotic Fluid, DNA extraction, Cytogenetic Analysis, Gestation, Medicine, lcsh:Q, Female, Cytogenetic Techniques, Comparative genomic hybridization, Research Article, Test Evaluation
Abstract: The aim of this study was to develop an improved technique for DNA extraction from 1 ml of uncultured AF from patients with a gestational age less than 16 weeks and to allow the use of array-CGH without DNA amplification. The DNA extraction protocol was tested in a series of 90 samples including 41 of uncultured AF at less than 16 weeks of gestation. Statistical analyses were performed using linear regression. To evaluate the sensitivity and the specificity of array-CGH on 1 ml of uncultured AF, five samples with an abnormal karyotype (three with aneuploidy, two with structural abnormalities) and five with a normal karyotype were studied. This protocol was reproducible and we were able to show a great improvement with higher yield of DNA obtained from all patients, including those with a gestational age less than 16 weeks (p = 0.003). All chromosomal abnormalities were detected and characterized by array-CGH and normal samples showed normal profiles. This new DNA extraction protocol associated with array-CGH analysis could be used in prenatal testing even when gestational age is less than 16 weeks, especially in cases with abnormal ultrasound findings.
Published: 2012

44. Homozygous SMN1 exons 1-6 deletion: pitfalls in genetic counseling and general recommendations for spinal muscular atrophy molecular diagnosis

Author: Mireille Cossée, Pierre Soichot, Alice Masurel-Paulet, M. Antin, J.V. De Monleon, Nadège Calmels, Frédéric Huet, Bénédicte Gérard, P. Saugier Veber, Séverine Drunat, Paul Sagot, C. Thauvin-Robinet, D. Chantereau, le 'réseau français de génétique moléculaire', Laurence Faivre, and C. Cassini
Subjects: Genetic counseling, Genetic Counseling, SMN1, Biology, Muscular Atrophy, Spinal, Exon, Genetics, medicine, Humans, Allele, Gene, Genetics (clinical), Alleles, Homozygote, Chromosome Mapping, Infant, Spinal muscular atrophy, Exons, medicine.disease, SMA, Survival of Motor Neuron 1 Protein, nervous system diseases, Pedigree, Human genome, Female, Gene Deletion
Abstract: We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a patient with spinal muscular atrophy (SMA) born into a consanguineous family. This exceptional configuration induced misinterpretation of the molecular defect involved in this patient, who was first reported as having a classic SMN1 exon 7 deletion. This case points out the possible pitfalls in molecular diagnosis of SMA in affected patients and their relatives: exploration of the SMN1 exon 7 (c.840C/T alleles) may be disturbed by several non-pathological or pathological variants around the SMN1 exon 7. In order to accurately describe the molecular defect in an SMA-affected patient, we propose to apply the Human Genome Variation Society nomenclature. This widely accepted nomenclature would improve the reporting of the molecular defect observed in SMA patients and thus would avoid the commonly used but imprecise terminology "absence of SMN1 exon 7."
Published: 2011

45. Exposure to hydroxyurea during pregnancy: a case series

Author: E Robert, Rene-Olivier Casasnovas, H. Guy, C Maingueneau, S Douvier, A Nivelon-Chevallier, Denis Caillot, E Elefant, and C Thauvin-Robinet
Subjects: Cancer Research, Pregnancy, Maternal-fetal exchange, Series (stratigraphy), medicine.medical_specialty, Myeloproliferative Disorders, business.industry, Obstetrics, Pregnancy Complications, Hematologic, Pregnancy Outcome, MEDLINE, Hematology, medicine.disease, Oncology, Maternal Exposure, Humans, Hydroxyurea, Medicine, Female, business, Maternal-Fetal Exchange, Pregnancy Complications, Neoplastic
Published: 2001

46. Vertebral defects as an unusual mode of presentation of 22q11.2 deletion

Author: L. Faivre, A. Masurel-Paulet, P. Callier, N. Mejean, S. Gay, M. Grimaldi, F. Mugneret, F. Huet, and C. Thauvin-Robinet
Subjects: Genetics, Adult, Male, Pregnancy, Chromosomes, Human, Pair 22, Infant, Newborn, Infant, Anatomy, Biology, medicine.disease, Infant newborn, Spine, Vertebra, Radiography, medicine.anatomical_structure, Immunopathology, medicine, Humans, Female, Presentation (obstetrics), Chromosome Deletion, Genetics (clinical)
Published: 2009

47. [Variations in the prevalence of Down's syndrome in the French population between 1978 and 2005]

Author: T, Rousseau, E, Amar, C, Ferdynus, C, Thauvin-Robinet, J-B, Gouyon, and P, Sagot
Subjects: Adult, Adolescent, Infant, Newborn, Abortion, Induced, Middle Aged, Young Adult, Pregnancy, Prenatal Diagnosis, Prevalence, Humans, Female, France, Down Syndrome, Live Birth, Maternal Age
Abstract: To evaluate the impact of maternal age and prenatal diagnosis on the prevalence of Down's syndrome at birth in French population sample.Data concerning Down's syndrome from 1978 to 2005 were obtained from the REMERA registry of congenital malformations. The population surveyed was approximately 10% of French births. We studied total prevalence, live-birth prevalence and the prevalence of pregnancy termination after prenatal diagnosis.Mean maternal age has risen from 26 to 30 years over the study period. Total prevalence of Down's syndrome has increased from 14 per 10,000 in 1978 to 23 per 10,000 live-births in 2005. Termination of pregnancy after prenatal diagnosis of Down's syndrome gradually increased reaching 78% in 2005. Live-birth prevalence decreased from 14 per 10,000 in 1978 to 5.1 per 10,000 in 2005.This work shows the importance of continuing the epidemiological survey of Down's syndrome in France, especially because of the modification in population ageing as well in prenatal screening policies for Down's syndrome.
Published: 2009

48. [Impact of maternal age distribution on the expected live birth prevalence of Down's syndrome in the metropolitan France between 1965 and 2008]

Author: T, Rousseau, C, Ferdynus, C, Thauvin-Robinet, J-B, Gouyon, and P, Sagot
Subjects: Adult, Adolescent, Infant, Newborn, Middle Aged, Young Adult, Pregnancy, Prenatal Diagnosis, Prevalence, Humans, Female, France, Down Syndrome, Live Birth, Maternal Age
Abstract: To evaluate the impact of demographic factors such as maternal age on the expected prevalence of Down's syndrome at birth.We used data from the French National Institute of Statistics (INSEE) concerning live births and maternal age. Expected prevalence at birth is derived from a mathematical regression model commonly used in biochemical screening.We present continuous expected prevalence at birth over a long period, from 1965 to 2008. Over the last three decades, mean maternal age has increased by 4 years, leading to a two-fold increased in the expected live-birth prevalence of Down's syndrome infants, from 12.1 per 10,000 in 1977 to 21.7 per 10,000 in 2008.It is important to continue to consider the impact modifications in demographic factors, such as maternal age, particularly in the evaluation of screening practices and policies for Down's syndrome.
Published: 2009

49. [Genetic testing in asymptomatic minors: a survey among French geneticists]

Author: L, Joly, C, Thauvin-Robinet, F, Huet, J-M, Pinoit, A, Contrain, C, Cassini, F, Coron, E, Gautier, B, Bonin, M, Gargiulo, D, Heron, A, Dürr, L, Faivre, and L, Tourtelier
Subjects: Adult, Male, Minors, Parents, Adolescent, Attitude of Health Personnel, Surveys and Questionnaires, Humans, Female, France, Genetic Testing, Middle Aged
Abstract: Since their introduction, genetic tests have been carefully considered, with special attention to the release of information about the test and test results, the confidentiality of genetic information, the request and its motivation, and the psychological impact of the test. Careful consideration is needed when family members at risk are asymptomatic children or adolescents. Cautious reflection is warranted on whether and under which conditions genetic testing should be performed. Here, we report on the results of a survey conducted in France among 50 geneticists questioned on their opinions and practices concerning presymptomatic testing in three groups of diseases: those for which a medical benefit exists during childhood (e.g., retinoblastoma), diseases with onset during childhood for which there are no immediate medical consequences (e.g., type II/III spinal muscular atrophy), and those with onset during adulthood for which there is no medical benefit during childhood (e.g., Huntington disease). Guidelines are proposed: presymptomatic testing should not be performed in a minor without individual and direct information, all requests for presymptomatic genetic testing concerning a disease with onset in adulthood should be postponed, and all presymptomatic test requests for a minor should be addressed to a multidisciplinary team.
Published: 2009

50. The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum

Author: Thibault Moreau, Frédéric Sedel, D. Perennou, M.-H. Horellou, C. Tonneti, Alice Masurel-Paulet, Emmanuel Roze, C. Thauvin-Robinet, Stéphane Giraudier, G. Bruneteau, G. Couvreur, M. Giroud, D. Grabli, Laurence Faivre, H. Ogier de Baulny, 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 ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Motricité - Plasticité, Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pathology, DNA Mutational Analysis, MESH: Hydroxocobalamin, MESH: Brain Diseases, Metabolic, Inborn, Disease, MESH : Neurologic Examination, 0302 clinical medicine, Gene Duplication, Hydroxocobalamin, Child and adolescent psychiatry, Medicine, MESH: DNA Mutational Analysis, MESH : Amino Acid Metabolism, Inborn Errors, 0303 health sciences, MESH: Gene Duplication, Brain, MESH : Infusions, Intravenous, MESH: Follow-Up Studies, 3. Good health, Psychiatry and Mental health, Spinal Cord, Homocystinuria, MESH : Carrier Proteins, MESH: Homocystinuria, medicine.medical_specialty, MESH : Injections, Intramuscular, MESH : Gene Duplication, MESH: Methylmalonic Acid, MESH: Carrier Proteins, MESH : DNA Mutational Analysis, 03 medical and health sciences, MESH : Adolescent, MESH : Magnetic Resonance Imaging, Humans, MESH: Amino Acid Metabolism, Inborn Errors, MESH: Genes, Recessive, Chromosome Aberrations, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, MESH : Humans, Brain Diseases, Metabolic, Inborn, MESH : Genes, Recessive, MESH: Adult, MESH : Follow-Up Studies, MMACHC, MESH : Brain, Surgery, MESH: Cerebral Ventricles, Neurology (clinical), Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, MESH : Mutation, Missense, Pediatrics, Compound heterozygosity, Cerebral Ventricles, MESH: Magnetic Resonance Imaging, MESH: Spinal Cord, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Missense mutation, MESH: Neurologic Examination, MESH : Female, Infusions, Intravenous, Neurologic Examination, medicine.diagnostic_test, Genetic Carrier Screening, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH : Adult, Magnetic Resonance Imaging, MESH: Injections, Intramuscular, MESH : Methylmalonic Acid, Female, MESH : Cerebral Ventricles, Oxidoreductases, Adult, Adolescent, MESH : Male, MESH : Chromosome Aberrations, Mutation, Missense, Genes, Recessive, MESH : Brain Diseases, Metabolic, Inborn, Injections, Intramuscular, MESH: Brain, MESH : Heterozygote Detection, Neuroimaging, MESH: Chromosome Aberrations, MESH: Infusions, Intravenous, Amino Acid Metabolism, Inborn Errors, 030304 developmental biology, MESH: Heterozygote Detection, MESH : Homocystinuria, MESH : Hydroxocobalamin, business.industry, Magnetic resonance imaging, MESH : Spinal Cord, MESH: Male, CBLC, business, Follow-Up Studies, Methylmalonic Acid
Abstract: International audience; BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.
Published: 2008

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