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46 results on '"Jean-Luc Alessandri"'

1. First Description of a Large Clinical Series of Fetal Alcohol Spectrum Disorders Children and Adolescents in Reunion Island, France

Author: Laëtitia Sennsfelder, Susie Guilly, Sonia Henkous, Christophe Lebon, Sébastien Leruste, Pauline Beuvain, Fanny Ferroul, Stéphanie Benard, Frédérique Payet, Meissa Nekaa, Maité Bagard, Magaly Lauret, Virginie Hoareau, Aurélie Caillier, Stéphanie Robin, Justine Lanneaux, Léa Etchebarren, Michel Spodenkiewicz, Jean-Luc Alessandri, Godelieve Morel, and Bérénice Roy-Doray
Subjects: fetal alcohol spectrum disorders, clinical description, Reunion Island, Pediatrics, RJ1-570
Abstract: Background: Despite several diagnostic guidelines, Fetal Alcohol Spectrum Disorders (FASDs) remain underdiagnosed or misdiagnosed, delaying the care of these patients and support for families. Objective: This study aims to help professionals caring for these children and their families to suspect this diagnosis earlier and to provide the most appropriate follow-up. Methods: A retrospective chart review with monocentric recruitment was performed at the Genetics Unit of the University Hospital of Reunion Island. A total of 147 children and adolescents with FASDs were included. Results: Prenatal alcohol exposure was associated with paternal alcohol consumption in 42.9%, and a high rate of prematurity (33.3%) was observed. Sixty percent of children or adolescents were placed in foster families. Learning difficulties without cognitive deficits were found in 65.8% of cases (50/76). Postural control and fine motor skills disabilities were described, respectively, in 54.7% (35/64) and 72.5% (50/69) of cases. A systematic genetic assessment was carried out, identifying in these FASD patients an associated Copy Number Variation (CNVs) in 22.6% of cases. Conclusion: Children with FASDs combine significant vulnerabilities, associating exposure to alcohol during the preconception and/or the prenatal period, prematurity, complex familial and sociocultural living conditions, and a genetic anomaly in almost a quarter of cases.
Published: 2024
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2. Description of Copy Number Variations in a Series of Children and Adolescents with FASD in Reunion Island

Author: Laëtitia Sennsfelder, Susie Guilly, Sébastien Leruste, Ludovic Hoareau, Willy Léocadie, Pauline Beuvain, Meïssa Nekaa, Maïté Bagard, Stéphanie Robin, Justine Lanneaux, Léa Etchebarren, Marilyn Tallot, Michel Spodenkiewicz, Jean-Luc Alessandri, Godelieve Morel, Maud Blanluet, Paul Gueguen, and Bérénice Roy-Doray
Subjects: fetal alcohol spectrum disorder, copy number variation, chromosomal analysis on DNA chip, Pediatrics, RJ1-570
Abstract: Background: Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of neurocognitive impairment and social inadaptation, affecting 1 birth in 100. Despite the existence of precise diagnostic criteria, the diagnosis remains difficult, often confounded with other genetic syndromes or neurodevelopmental disorders. Since 2016, Reunion Island has been a pilot region for the identification, diagnosis, and care of FASD in France. Objective: To evaluate the prevalence and the types of Copy Number Variations (CNV) in FASD patients. Methods: A retrospective chart review of 101 patients diagnosed with FASD in the Reference Center for developmental anomalies and in the FASD Diagnostic Center of the University Hospital was performed. Records of all patients were reviewed to obtain their medical history, family history, clinical phenotype, and investigations, including genetic testing (CGH- or SNP-array). Results: A rate of 20.8% (n = 21) of CNVs was found including 57% (12/21) of pathogenic variants and 29% (6/21) of variants of uncertain signification (VUS). Conclusion: A particularly high number of CNVs was found in children and adolescents with FASD. It reinforces the plea for a multidisciplinary approach for developmental disorders to explore both environmental factors, such as avoidable teratogens and intrinsic vulnerabilities, especially genetic determinants.
Published: 2023
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3. The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders

Author: Julian Delanne, Ange-Line Bruel, Frédéric Huet, Sébastien Moutton, Sophie Nambot, Margot Grisval, Nada Houcinat, Paul Kuentz, Arthur Sorlin, Patrick Callier, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Daphné Lehalle, Salima El Chehadeh, Christine Francannet, Marine Lebrun, Laetitia Lambert, Marie-Line Jacquemont, Marion Gerard-Blanluet, Jean-Luc Alessandri, Marjolaine Willems, Julien Thevenon, Mondher Chouchane, Véronique Darmency, Clémence Fatus-Fauconnier, Sébastien Gay, Marie Bournez, Alice Masurel, Vanessa Leguy, Yannis Duffourd, Christophe Philippe, François Feillet, Laurence Faivre, and Christel Thauvin-Robinet
Subjects: Inherited metabolic disorders, Exome sequencing, Intellectual disability, Developmental delay, Genotype first, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable. Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
Published: 2021
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4. Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation.

Author: Valentina Grampa, Marion Delous, Mohamad Zaidan, Gweltas Odye, Sophie Thomas, Nadia Elkhartoufi, Emilie Filhol, Olivier Niel, Flora Silbermann, Corinne Lebreton, Sophie Collardeau-Frachon, Isabelle Rouvet, Jean-Luc Alessandri, Louise Devisme, Anne Dieux-Coeslier, Marie-Pierre Cordier, Yline Capri, Suonavy Khung-Savatovsky, Sabine Sigaudy, Rémi Salomon, Corinne Antignac, Marie-Claire Gubler, Alexandre Benmerah, Fabiola Terzi, Tania Attié-Bitach, Cécile Jeanpierre, and Sophie Saunier
Subjects: Genetics, QH426-470
Abstract: Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.
Published: 2016
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5. Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: the CHIMERE cohort study on Reunion Island.

Author: Patrick Gérardin, Sylvain Sampériz, Duksha Ramful, Brahim Boumahni, Marc Bintner, Jean-Luc Alessandri, Magali Carbonnier, Isabelle Tiran-Rajaoefera, Gilles Beullier, Irénée Boya, Tahir Noormahomed, Jocelyn Okoï, Olivier Rollot, Liliane Cotte, Marie-Christine Jaffar-Bandjee, Alain Michault, François Favier, Monique Kaminski, Alain Fourmaintraux, and Xavier Fritel
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection.The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ ≤ 85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms.The mean DQ score was 86.3 (95%CI: 81.0-91.5) in infected children compared to 100.2 (95%CI: 98.0-102.5) in uninfected peers (P
Published: 2014
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6. Congenital Syphilis, Réunion Island, 2010

Author: Juliana Ramiandrisoa, Lydéric Aubert, Emilie Boidin Lespine, Jean-Luc Alessandri, Pierre-Yves Robillard, Marc Bertsch, Anne Gallay, Véronique Goulet, and Eric D’Ortenzio
Subjects: syphilis, Treponema pallidum, congenital, Indian Ocean, Réunion Island, mass screening, Medicine, Infectious and parasitic diseases, RC109-216
Published: 2011
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7. Lessons from two series by physicians and caregivers’ self-reported data, and DNA methylation profile in DDX3X-Related Disorders

Author: David Geneviève, Valentin Ruault, Pauline Burger, Johanna Gradels-Hauguel, Nathalie Ruiz-Pallares, Xtraordinaire Association, Rami Abou Jamra, Alexandra Afenjar, Yves Alembik, Jean-Luc Alessandri, Arpin Stéphanie, Giulia Barcia, Šárka Bendová, Ange-Line Bruel, Perrine Charles, Nicolas Chatron, Maya Chopra, Solène Conrad, Valérie Cormier-Daire, Auriane Cospain, Christine Coubes, Juliette Coursimault, Andrée Delahaye-Duriez, Martine Doco-Fenzy, William Dufour, Benjamin Durand, Camille ENGEL, Laurence Faivre, Fanny Ferroul, Mélanie FRADIN, Hélène Frenkiel, Carlo Fusco, Livia Garavelli, Aurore Garde, Bénédicte Gérard, David Germanaud, Louise Goujon, Aurélie Gouronc, Emmanuelle Ginglinger, Alice Goldenberg, Miroslava Hancarova, Delphine Héron, Bertrand Isidor, Nolwenn Jean Marçais, Boris Keren, Margarete Koch-Hogrebe, Paul Kuentz, Victoria Lamure, Anne-Sophie Lebre, François Lecoquierre, Natacha Lehman, Gaetan Lesca, Stanislas Lyonnet, Delphine Martin, Cyril Mignot, Teresa Neuhann, Gaël Nicolas, Mathilde Nizon, Florence Petit, Christophe Philippe, Amélie Piton, Marzia Pollazzon, Darina Prchalova, Audrey Putoux, Marlène RIO, Sophie Rondeau, Massimiliano Rossi, Quentin Sabbagh, Pascale Saugier-Veber, Ariane Schmetz, Julie Steffann, Christel Thauvin-Robinet, Annick Toutain, Frédéric Tran-Mau-Them, Gabriele Trimarchi, Marie Vincent, Marketa Vlckova, Dagmar Wieczorek, Marjolaine Willems, kevin yauy, Michaela Zelinová, Alban Ziegler, Boris Chaumette, Bekim Sadikovic, and Jean-Louis Mandel
Abstract: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.
Published: 2023

8. First Case of Acute Myocarditis Caused by Metapneumovirus in an Immunocompromised 14-year-old Girl

Author: Anissa Makhlouf, Lise Peipoch, Pauline Duport, Etienne Darrieux, Yves Reguerre, Duksha Ramful, Jean-Luc Alessandri, and Yael Levy
Subjects: Critical Care and Intensive Care Medicine
Published: 2022

9. Clinical and neuroimaging findings in 33 patients with <scp>MCAP</scp> syndrome: A survey to evaluate relevant endpoints for future clinical trials

Author: Florence Petit, Fabienne Giuliano, Juliette Mazereeuw-Hautier, Marjolaine Willems, Christel Thauvin-Robinet, Patricia Blanchet, Laurence Faivre, Elodie Gautier, Anne-Claire Bursztejn, Renaud Touraine, Annick Toutain, Frederico Di Rocco, Maxime Luu, Patrick Edery, Arthur Sorlin, Jean-Luc Alessandri, Nicolas Chassaing, Alice Goldenberg, Christine Chiaverini, Fanny Morice-Picard, Aurore Garde, Stéphanie Arpin, Massimiliano Rossi, Marc Bardou, Claire Nicolas, Gilles Morin, Jenny Cornaton, Cyril Mignot, Christophe Philippe, V. Carmignac, Rodolphe Dard, Joelle Roume, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Pierre Vabres, Didier Lacombe, Diane Doummar, Lucile Pinson, Christine Coubes, Laurent Guibaud, Olivia Boccara, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cutis marmorata, Adolescent, Class I Phosphatidylinositol 3-Kinases, Neuroimaging, Context (language use), Skin Diseases, Vascular, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Genetics, Polymicrogyria, medicine, Humans, PROS, Abnormalities, Multiple, Telangiectasis, Megalencephaly, Child, MCAP syndrome, Genetics (clinical), Chiari malformation, Clinical Trials as Topic, business.industry, Macrocephaly, PIK3CA, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Clinical trial, 030104 developmental biology, Child, Preschool, Postnatal macrocephaly, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Forecasting, Ventriculomegaly
Abstract: Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
Published: 2021

10. Differentiating Enteroviral Meningitis from Bacterial Meningitis in Neonates

Author: Stéphanie Robin, Nicolas Traversier, Marie Gromand, Vincent Luherne, Jean-Luc Alessandri, Duksha Ramful, and Shelley Harrikaran-Biland
Subjects: medicine.medical_specialty, business.industry, Birth weight, medicine.disease_cause, Procalcitonin, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Cerebrospinal fluid, CSF pleocytosis, 030225 pediatrics, Internal medicine, Pediatrics, Perinatology and Child Health, Hypoglycorrhachia, Medicine, Enterovirus, Bacterial meningitis, 030212 general & internal medicine, Abnormality, business
Abstract: Objective To compare the demographical, clinical and laboratory features, and outcomes of neonates with enteroviral meningitis (EVM) with those with bacterial meningitis (BM). Methods A retrospective two-center study was performed in La Réunion Island between January 2008 and December 2018 in hospitalized neonates aged less than 29 days. Patients positive for enterovirus real-time polymerase chain reaction from the cerebrospinal fluid (CSF) were diagnosed with EVM. Neonates with positive CSF culture results for a potentially pathogenic bacterium were diagnosed with BM. Results Compared with their EVM peers (n = 20), BM-infected neonates (n = 14) had lower birth weight, and were more likely to present hypotension and neurological symptoms on admission. Thrombocytopenia, elevated serum procalcitonin, hyperproteinorachia, hypoglycorrhachia, CSF pleocytosis, a bacterial meningitis score >0 were more frequent in the BM-infected group. All BM-infected neonates had at least one abnormal cutoff value in the CSF, while nine neonates (45%) in the EVM group had no CSF abnormality (p = 0.004). BM-infected neonates also had a longer length of hospital stay, needed more supportive care, received more prolonged antimicrobial courses, and developed respiratory and neurological complications. Conclusion Recognition of some clinical and laboratory features can help clinicians in differentiating BM from EVM when managing this high-risk patient group.
Published: 2020

11. STAC3 related congenital myopathy: A case series of seven Comorian patients

Author: Marie Gromand, Paul Gueguen, Anne Pervillé, Fanny Ferroul, Godelieve Morel, Anrifati Harouna, Bérénice Doray, J. Andoni Urtizberea, Jean-Luc Alessandri, and Stéphanie Robin
Subjects: Muscular Diseases, Myotonia Congenita, Genetics, Humans, General Medicine, Malignant Hyperthermia, Genetics (clinical), Excitation Contraction Coupling, Adaptor Proteins, Signal Transducing
Abstract: The Bailey-Bloch congenital myopathy, also known as Native American myopathy (NAM), is an autosomal recessive congenital myopathy first reported in the Lumbee tribe people settled in North Carolina (USA), and characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia. NAM is linked to STAC3 gene coding for a component of excitation-contraction coupling in skeletal muscles. A homozygous missense variant (c.851G C; p.Trp284Ser) in STAC3 segregated with NAM in the Lumbee families. Non-Native American patients with STAC3 related congenital myopathy, and with other various variants of STAC3 have been reported. Here, we present seven patients from the Comoros Islands (located in the Mozambique Channel) diagnosed with STAC3 related congenital myopathy and having the recurrent variant identified in the Lumbee people. The series is the second largest series of patients having STAC3 related congenital myopathy with a shared ethnicity after le Lumbee series. Local history and geography may explain the overrepresentation of NAM in the Comorian Archipelago with a founder effect. Further researches would be necessary for the understanding of the onset of the NAM in Comorian population as search of the "classical" STAC3 variant in East African population, and haplotypes comparison between Comorian and Lumbee patients.
Published: 2022

12. SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature

Author: Bertrand Isidor, Kimberly A. Aldinger, Valérie Cormier-Daire, Sophie Rondeau, William B. Dobyns, Boris Keren, Pauline Marzin, Jean Luc Alessandri, and Delphine Héron
Subjects: Male, Joint hypermobility, Pediatrics, medicine.medical_specialty, Intellectual disability, Genetics, Humans, Medicine, Missense mutation, Child, Growth Disorders, Genetics (clinical), Sotos Syndrome, business.industry, Macrocephaly, Infant, Histone-Lysine N-Methyltransferase, medicine.disease, Autism spectrum disorder, Child, Preschool, Overgrowth syndrome, Mutation, Speech delay, Autism, Female, medicine.symptom, business
Abstract: The common genes responsible for overgrowth syndromes play key roles in regulating transcription through histone modification and chromatin modeling. The SETD2 gene encoding a H3K36 trimethyltransferase is implicated in Sotos-like syndrome. This syndrome is characterized by postnatal overgrowth, macrocephaly, obesity, speech delay, and advanced carpal ossification. We report four new patients with constitutional SETD2 mutations and review nine earlier reported patients. Almost all patients presented with macrocephaly associated with advanced stature and obesity in half of the cases. In addition to these principal manifestations, neurodevelopmental disorders are common such as intellectual disability (83%), autism spectrum disorders (89%), and behavioral difficulties (100%) with aggressive outbursts (83%). A variety of features such as joint hypermobility (29%), hirsutism (33%), and naevi (50%) were also reported. Constitutional SETD2 mutations are intragenic loss-of-function variants with truncating (69%) and missense (31%) mutations. Functional studies are necessary to improve understanding of the pathogenicity of some missense SETD2 mutations.
Published: 2019

13. Author response for 'Clinical and neuroimaging findings in 33 patients with MCAP syndrome: a survey to evaluate relevant endpoints for future clinical trials'

Author: Florence Petit, Juliette Mazereeuw-Hautier, Christine Coubes, Patricia Blanchet, Jenny Cornaton, Frederico Di Rocco, Fabienne Giuliano, Arthur Sorlin, Elodie Gautier, Laurent Guibaud, Renaud Touraine, Massimiliano Rossi, Christophe Philippe, Jean-Luc Alessandri, Joelle Roume, Patrick Edery, Gilles Morin, Christine Chiaverini, Diane Doummar, Michèle Mathieu-Dramard, Olivia Boccara, Philippe Khau Van Kien, Aurore Garde, Claire Nicolas, Maxime Luu, Lucile Pinson, Nicolas Chassaing, Fanny Morice-Picard, Christel Thauvin-Robinet, Rodolphe Dard, Cyril Mignot, Marc Bardou, V. Carmignac, Pierre Vabres, Alice Goldenberg, Laurence Faivre, Didier Lacombe, Annick Toutain, Stéphanie Arpin, Marjolaine Willems, and Anne-Claire Bursztejn
Subjects: Clinical trial, medicine.medical_specialty, Neuroimaging, business.industry, medicine, Intensive care medicine, business
Published: 2020

14. High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3

Author: Sophie Scheidecker, Hugues Flodrops, Jean-Luc Alessandri, Corinne Stoetzel, Aurélie Gouronc, Hélène Dollfus, Manuela Antin, Paul Gueguen, Marie-Line Jacquemont, Bérénice Doray, Françoise Darcel, Frédérique Payet, Hanitra Randrianaivo, Vincent Zilliox, Jean Muller, Elsa Nourisson, and Anne-Sophie Leuvrey
Subjects: 0301 basic medicine, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Genetic counseling, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Bardet–Biedl syndrome, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Genotyping, Bardet-Biedl Syndrome, Genetics (clinical), Alleles, Polydactyly, ADP-Ribosylation Factors, Haplotype, medicine.disease, Founder Effect, Pedigree, Ciliopathy, 030104 developmental biology, Haplotypes, Child, Preschool, Mutation, Female, Founder effect, SNP array
Abstract: Bardet-Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Reunion Island using sequencing (Sanger and high-throughput methods) and SNP array. In eight families (12 individuals) we identified the same ARL6/BBS3 variation [c.535G > A, p.(Asp179Asn)]. Bioinformatics and functional analyses revealed an effect of this variant on the splicing of ARL6/BBS3. Owing to the relatively high frequency of this variant, a possible founder effect was suspected. Genotyping of six individuals revealed a common 3.8-Mb haplotype and estimated the most recent common ancestor to about eight generations confirmed by the known genealogy. Knowledge of this founder effect modifies our diagnostic strategy and enables a personalized genetic counseling for patients from La Reunion Island. Being the first description of BBS patients from La Reunion Island, we could estimate its prevalence between ~1/45000 and ~ 1/66000 individuals.
Published: 2020

15. A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis

Author: Dominique Bonneau, Bruno Delobel, Catherine Boileau, Guillaume Jondeau, Christine Coubes, Jean-Luc Alessandri, Laurence Faivre, V. Carmignac, Sylvie Odent, Pauline Arnaud, Christel Thauvin-Robinet, Nadine Hanna, Caroline Racine, Carine Le Goff, Julien Thevenon, Laurent Gouya, Jill Clayton-Smith, Sophie Dupuis-Girod, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Université de Paris, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Grenoble, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Hospices Civils de Lyon (HCL), 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 ), CHU Pontchaillou [Rennes], 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, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), 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, Burgundy Regional Council through the Plan d'Actions Regional pour l'Innovation (PARI 2015), European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs, Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, 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), 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), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), 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, Proband, Marfan syndrome, Connective Tissue Disorder, Adolescent, [SDV]Life Sciences [q-bio], Context (language use), Biology, Marfan Syndrome, Craniosynostoses, 03 medical and health sciences, Proto-Oncogene Proteins, Intellectual disability, Genetics, medicine, Humans, Pathology, Molecular, Craniofacial, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Marfanoid, Middle Aged, medicine.disease, Human genetics, 3. Good health, DNA-Binding Proteins, Arachnodactyly, Child, Preschool, Mutation, Female
Abstract: International audience; SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
Published: 2020

16. Epidemiology of achondroplasia: A population-based study in Europe

Author: Anke Rissmann, Jorieke E. H. Bergman, Nathalie Lelong, Olatz Mokoroa, Florence Rouget, Nataliia Zymak-Zakutnia, Clara Cavero-Carbonell, Michele Santoro, Amanda J. Neville, Kari Klungsøyr, Marie-Claude Addor, Ingeborg Barisic, Diana Wellesley, Ljubica Boban, Karen Luyt, Isabelle Perthus, Martin Haeusler, Judith Rankin, David Tucker, Vera Nelen, Miriam Gatt, J. J. Kurinczuk, Fabrizio Bianchi, Alessio Coi, Mary O'Mahony, Jean-Luc Alessandri, Carmel Mullaney, Paula Braz, Anna Pierini, Bruno Schaub, Katarzyna Wisniewska, Monica Lanzoni, Ester Garne, Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Maison de la Femme de la Mère et de l'Enfant [CHU de la Martinique] (MFME [Fort de France]), CHU de la Martinique [Fort de France], JRC‐EUROCAT Central Registry, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Reproductive Origins of Adult Health and Disease (ROAHD)
Subjects: Adult, Male, medicine.medical_specialty, Pediatrics, Thanatophoric dysplasia, paternal age, [SDV]Life Sciences [q-bio], Population, prevalence, THANATOPHORIC DYSPLASIA, Prenatal diagnosis, skeletal dysplasia, 03 medical and health sciences, Rare Diseases, Pregnancy, EUROCAT, Prenatal Diagnosis, Epidemiology, achondroplasia, Genetics, medicine, Humans, Achondroplasia, Fetal Death, Genetics (clinical), 030304 developmental biology, 0303 health sciences, business.industry, MORTALITY, epidemiology, 030305 genetics & heredity, RENAC, Genetic disorder, Infant, Newborn, Pregnancy Outcome, medicine.disease, Observação em Saúde e Vigilância, Estados de Saúde e de Doença, 3. Good health, Europe, Dysplasia, Population study, Female, business, Anomalias Congénitas, Maternal Age
Abstract: Achondroplasia is a rare genetic disorder resulting in short-limb skeletal dysplasia. We present the largest European population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991-2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14-4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011-2015 vs. 36% in 1991-1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia. Funding for the JRC-EUROCAT Central Registry is described in Kinsner-Ovaskainen et al. (2018). We thank Prof. Joan Morris (St. George's University of London) for her helpful suggestions. info:eu-repo/semantics/publishedVersion
Published: 2019

17. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author: Sophie Scheidecker, Françoise Devillard, Gaetan Lesca, Maryline Carneiro, Christèle Dubourg, Ganaëlle Remerand, Catherine Badens, Odile Boespflug-Tanguy, Nathalie Marle, Serge Romana, Nadia Bahi-Buisson, Jean-Paul Bonnefont, Hubert Journel, Bénédicte Duban-Bedu, Brigitte Gilbert-Dussardier, Mathilde Nizon, Nathalie Perreton, Sophie Julia, Cyril Goizet, Delphine Héron, Véronique Satre, Marguerite Miguet, Joris Andrieux, Pierre-Simon Jouk, Laurence Perrin, Renaud Touraine, Ghislaine Plessis, Dominique Martin-Coignard, Caroline Rooryck, Catherine Vincent-Delorme, Laurence Faivre, Salima El Chehadeh, Thierry Bienvenu, Jean-Luc Alessandri, Anne-Claude Tabet, Laurent Pasquier, Martine Raynaud, Réseau AChro-Puce, Marjolaine Willems, Bruno Leheup, Marianne Till, Jeanne Amiel, Jacqueline Vigneron, Nicole Philip, Valérie Kremer, Massimiliano Rossi, Boris Keren, Annick Toutain, Fabienne Prieur, Bertrand Isidor, Séverine Drunat, Marilyn Lackmy-Port-Lis, Albert David, Christel Thauvin-Robinet, Damien Sanlaville, Laetitia Lambert, Lydie Burglen, Klaus Dieterich, Catherine Sarret, Anne Moncla, Didier Lacombe, Fanny Laffargue, Kim Maincent, Marlène Rio, Clarisse Baumann, Mathilde Lefebvre, Sabine Sigaudy, Laurent Guibaud, Adeline Vigouroux, Valérie Malan, Patrick Callier, Chantal Missirian, Christophe Philippe, Christine Francannet, Anne-Laure Mosca-Boidron, Valérie Cormier-Daire, Cédric Le Caignec, Vincent des Portes, Charles Coutton, Alexandra Afenjar, Sandrine Chantot-Bastaraud, Julien Thevenon, Mylène Béri-Dexheimer, Hilde Van Esch, Bernard Echenne, Jean-Marie Cuisset, Jean-Michel Pedespan, 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), 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), Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Génétique Médicale (CHU de Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neuro-pédiatrie (CHRU de Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale, Hopital Jeanne de Flandre, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de génétique clinique [CHU Necker], Département de neurologie pédiatrique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service de génétique clinique [Debré], Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Service de Génétique Médicale du CHU de Bordeaux, 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), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), CIC 1407, Hospices Civils de Lyon (HCL), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], GHICL-Hôpital Saint Vincent de Paul, Service de Neuropédiatrie [CHU Necker - Enfants Malades], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, 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), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Service de Neurologie Pédiatrique [CHU Lyon], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre for Human Genetics, University Hospitals Leuven [Leuven], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de référence des déficiences intellectuelles de causes rares (Hospices Civils de Lyon), Hospices civils de Lyon (HCL), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Groupement Hospitalier Lyon-Est (GHE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MECP2 duplication syndrome, MECP2gene, Scoliosis, MECP2duplication syndrome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, Genetics, medicine, Spasticity, Genetics (clinical), X-linked, Vasomotor, business.industry, facial dysmorphism, medicine.disease, Gait, Hypotonia, 3. Good health, 030104 developmental biology, Xq28 duplication, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine.symptom, business, 030217 neurology & neurosurgery, genetic counselling
Abstract: The Xq28 duplication involving theMECP2gene (MECP2duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialMECP2duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofMECP2duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Published: 2018

18. Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Author: Edouard Cottereau, Annick Toutain, Estelle Colin, Marie-Pierre Moizard, Martine Raynaud, Sandrine Vonwill, Sylvie Rossignol, Fabienne Giuliano, Udhaya Kotecha, Tiffany Busa, Marie-Laure Vuillaume, Marion Gérard, Jean-Luc Alessandri, Frédéric Brioude, Mathilde Lefevre, Laetitia Lambert, Irène Netchine, Sheela Nampoothiri, Richard, Nicolas, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), IRCER - Axe 3 : organisation structurale multiéchelle des matériaux (IRCER-AXE3), Institut de Recherche sur les CERamiques (IRCER), Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Tours, Université de Tours (UT), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Unité de Génétique Clinique [CHRU Nancy], Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sir Ganga Ram Hospital, Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Human Molecular Genetics, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), IMAXIO, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital l'Archet, Service de Génétique Clinique Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: 0301 basic medicine, Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Genes, X-Linked, Genotype, Coding region, Missense mutation, MESH: Codon, Nonsense, Frameshift Mutation, Genetics (clinical), Genetics, 0303 health sciences, MESH: Frameshift Mutation, Genetic Diseases, X-Linked, Simpson–Golabi–Behmel syndrome, Pedigree, MESH: Arrhythmias, Cardiac, Phenotype, Codon, Nonsense, 030220 oncology & carcinogenesis, Female, Heart Defects, Congenital, MESH: Pedigree, Nonsense mutation, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Gigantism, Frameshift mutation, MESH: Intellectual Disability, 03 medical and health sciences, Glypicans, MESH: Glypicans, Intellectual Disability, medicine, MESH: Genetic Diseases, X-Linked, Humans, Simpson-Golabi-Behmel syndrome, Gene, overgrowth, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Arrhythmias, Cardiac, MESH: Heart Defects, Congenital, medicine.disease, mutations, MESH: Gigantism, MESH: Male, GPC3, X-linked disorder, 030104 developmental biology, MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Overgrowth syndrome, MESH: Female
Abstract: International audience; Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).
Published: 2018

19. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome

Author: Asma Chebil, Duksha Ramful, Thibaud Jouan, Hanitra Randrianaivo, Norbert F. Ajeawung, Nicolas Gruchy, Yannis Duffourd, Bérénice Doray, Christopher T. Gordon, Francesca Filippini, Christine Bole-Feysot, Philippe M. Campeau, Asma Omarjee, Julien Thevenon, Paul Kuentz, Jean-Luc Alessandri, Patrick Nitschke, Laurence Faivre, Jeanne Amiel, Coralie Dumont, Thi Tuyet Mai Nguyen, Marion Gérard, Myriam Oufadem, Guillaume Benoist, Olivier Alibeu, Marie-Line Jacquemont, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Sud Saint Pierre [Ile de la Réunion], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherche du CHU Sainte-Justine, CHU Sainte Justine [Montréal], Centre Hospitalier de Mayotte, 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, 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Service de réanimation néonatologique et pédiatrique [La Réunion], Groupe Hospitalier Sud-CHR La réunion, Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Pôle Gynécologie Obstétrique [CHM, Mayotte], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pôle Femme-Mère-Enfant [CHU La Réunion, Saint-Pierre, La Réunion], Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, 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 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire de Génétique Médicale ( LGM ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Université de Lausanne (UNIL), Laboratoire de Chimie Physique Macromoléculaire (LCPM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Equipe NuTox (LNC - U1231) (NUTOX), Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Maurice, Service de médecine foetale et foetopathologie, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), and University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC)
Subjects: 0301 basic medicine, Male, MESH: Limb Deformities, Congenital, Limb Deformities, Congenital, MESH: Phosphotransferases, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030105 genetics & heredity, Biology, MESH: Founder Effect, Article, 03 medical and health sciences, Pulmonary hypoplasia, 0302 clinical medicine, Fryns syndrome, Loss of Function Mutation, Genetics, medicine, Missense mutation, Humans, Allele, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Loss function, Hernia, Diaphragmatic, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Phosphotransferases, MESH: Infant, Newborn, Infant, Newborn, Congenital diaphragmatic hernia, Facies, Infant, MESH: Loss of Function Mutation, medicine.disease, MESH: Infant, Hypoplasia, Founder Effect, MESH: Male, MESH: Hernia, Diaphragmatic, MESH: Facies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Gene Deletion, Female, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Founder effect
Abstract: International audience; Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.
Published: 2018

20. Further delineation of the

Author: Marguerite, Miguet, Laurence, Faivre, Jeanne, Amiel, Mathilde, Nizon, Renaud, Touraine, Fabienne, Prieur, Laurent, Pasquier, Mathilde, Lefebvre, Julien, Thevenon, Christèle, Dubourg, Sophie, Julia, Catherine, Sarret, Ganaëlle, Remerand, Christine, Francannet, Fanny, Laffargue, Odile, Boespflug-Tanguy, Albert, David, Bertrand, Isidor, Jacqueline, Vigneron, Bruno, Leheup, Laetitia, Lambert, Christophe, Philippe, Mylène, Béri-Dexheimer, Jean-Marie, Cuisset, Joris, Andrieux, Ghislaine, Plessis, Annick, Toutain, Laurent, Guibaud, Valérie, Cormier-Daire, Marlene, Rio, Jean-Paul, Bonnefont, Bernard, Echenne, Hubert, Journel, Lydie, Burglen, Sandrine, Chantot-Bastaraud, Thierry, Bienvenu, Clarisse, Baumann, Laurence, Perrin, Séverine, Drunat, Pierre-Simon, Jouk, Klaus, Dieterich, Françoise, Devillard, Didier, Lacombe, Nicole, Philip, Sabine, Sigaudy, Anne, Moncla, Chantal, Missirian, Catherine, Badens, Nathalie, Perreton, Christel, Thauvin-Robinet, Réseau, AChro-Puce, Jean-Michel, Pedespan, Caroline, Rooryck, Cyril, Goizet, Catherine, Vincent-Delorme, Bénédicte, Duban-Bedu, Nadia, Bahi-Buisson, Alexandra, Afenjar, Kim, Maincent, Delphine, Héron, Jean-Luc, Alessandri, Dominique, Martin-Coignard, Gaëtan, Lesca, Massimiliano, Rossi, Martine, Raynaud, Patrick, Callier, Anne-Laure, Mosca-Boidron, Nathalie, Marle, Charles, Coutton, Véronique, Satre, Cédric Le, Caignec, Valérie, Malan, Serge, Romana, Boris, Keren, Anne-Claude, Tabet, Valérie, Kremer, Sophie, Scheidecker, Adeline, Vigouroux, Marilyn, Lackmy-Port-Lis, Damien, Sanlaville, Marianne, Till, Maryline, Carneiro, Brigitte, Gilbert-Dussardier, Marjolaine, Willems, Hilde, Van Esch, Vincent Des, Portes, and Salima, El Chehadeh
Subjects: Adult, Male, Chromosomes, Human, X, Epilepsy, Adolescent, Methyl-CpG-Binding Protein 2, Developmental Disabilities, Hypertension, Pulmonary, Infant, Stereotypic Movement Disorder, Pedigree, Young Adult, Hyperopia, Phenotype, Child, Preschool, Intellectual Disability, Mental Retardation, X-Linked, Somatosensory Disorders, Exotropia, Humans, France, Child
Abstract: The Xq28 duplication involving the
Published: 2017

21. Delineation ofEFTUD2Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients

Author: Marie Gonzales, Alice Goldenberg, Jean-Luc Alessandri, Charles Decaestecker, Alain Verloes, Daphné Lehalle, Marie-Line Jacquemont, Marlène Rio, Muriel Holder-Espinasse, Christopher T. Gordon, Alexandre Vasiljevic, Michel Vekemans, Loïc de Pontual, Sandrine Marlin, Laurent Pasquier, Didier Lacombe, Robert Smigiel, Lucile Boutaud, Sylvie Manouvrier-Hanu, Valérie Malan, Arnold Munnich, Jeanne Amiel, Stanislas Lyonnet, Christel Thauvin-Robinet, Roseline Caumes, Geneviève Baujat, Odile Boute-Benejean, Florence Petit, Myriam Oufadem, Gilles Morin, Neus Baena, Clarisse Baumann, Dominique Gaillard, Tania Attié-Bitach, Géraldine Goudefroye, and Michèle Mathieu-Dramard
Subjects: Male, Pediatrics, medicine.medical_specialty, Microcephaly, Hearing loss, Haploinsufficiency, Disease, Choanal atresia, Biology, Anus, Imperforate, Diagnosis, Differential, Hearing Loss, Bilateral, Pregnancy, Intellectual Disability, Prenatal Diagnosis, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Ear, External, Child, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Ophthalmoplegia, Infant, Peptide Elongation Factors, medicine.disease, External ear malformation, Thrombocytopenia, Phenotype, Child, Preschool, Atresia, Mutation, Female, medicine.symptom, Hand Deformities, Congenital, Mandibulofacial Dysostosis
Abstract: Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.
Published: 2014

22. À propos de six observations de double discordance cardiaque : faisabilité du diagnostic anténatal ?

Author: E. Julien, François Cartault, Fabrice Cuillier, Jean-Luc Alessandri, and Asma Omarjee
Subjects: Gynecology, medicine.medical_specialty, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics and Gynecology, Prenatal diagnosis, General Medicine, 030204 cardiovascular system & hematology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Reproductive Medicine, Medicine, business
Abstract: Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 42 - N° 2 - p. 143-150
Published: 2013

23. Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation

Author: Olivier Niel, Suonavy Khung-Savatovsky, Tania Attié-Bitach, Sabine Sigaudy, Emilie Filhol, Sophie Saunier, Yline Capri, Corinne Antignac, Sophie Collardeau-Frachon, Gweltas Odye, Mohamad Zaidan, Marion Delous, Sophie Thomas, Corinne Lebreton, Isabelle Rouvet, Valentina Grampa, Flora Silbermann, Rémi Salomon, Nadia Elkhartoufi, Alexandre Benmerah, Jean-Luc Alessandri, Marie-Pierre Cordier, Marie-Claire Gubler, Fabiola Terzi, Louise Devisme, Anne Dieux-Coeslier, Cécile Jeanpierre, Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Robert Debré, Laboratory of Intestinal Immunity (Equipe Inserm U1163), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Lille, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital de la Timone [CHU - APHM] (TIMONE), and Benmerah, Alexandre
Subjects: 0301 basic medicine, Cancer Research, Embryology, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, medicine.disease_cause, Kidney, Ciliopathies, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mice, Animal Cells, Medicine and Health Sciences, Morphogenesis, NIMA-Related Kinases, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Tissue homeostasis, Zebrafish, Connective Tissue Cells, Cystic kidney, Staining, Mutation, Polycystic Kidney Diseases, Cilium, Cell Staining, Nonsense Mutation, Cell Differentiation, 3. Good health, Hippo signaling, Connective Tissue, Female, Cellular Types, Anatomy, Cellular Structures and Organelles, Research Article, Signal Transduction, Porphyrins, Missense Mutation, lcsh:QH426-470, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Research and Analysis Methods, 03 medical and health sciences, Ciliogenesis, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Genetics, Animals, Humans, Cilia, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Hippo signaling pathway, [SDV.GEN]Life Sciences [q-bio]/Genetics, Embryos, Biology and Life Sciences, Verteporfin, Kidneys, YAP-Signaling Proteins, Cell Biology, Renal System, Fibroblasts, Phosphoproteins, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Nuclear Staining, lcsh:Genetics, 030104 developmental biology, Biological Tissue, Specimen Preparation and Treatment, Cancer research, Protein Kinases, Developmental Biology, Transcription Factors
Abstract: Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway., Author Summary Genes mutated in ciliopathies encode proteins with various localizations and functions at the primary cilium. Here we report novel NEK8 mutations in patients with renal cystic hypodysplasia and associated ciliopathy defects. NEK8 belongs to a protein complex defining the Inversin compartment of the cilium. It is also a negative regulator of the Hippo signaling pathway that controls organ growth. We report genotype-phenotype correlation in the patients. We functionally demonstrate that the two types of mutations (missense versus nonsense) differentially affect ciliogenesis, cell apoptosis and epithelialisation. We also show that all the mutations lead to dysregulation of the Hippo pathway through nuclear YAP imbalance but that the nature of this imbalance is different according to the type of mutation. We confirm alteration of the Hippo pathway associated with Nek8 mutation in vivo in Jck mice. Remarkably, we show that morphogenesis defects observed in Nek8 knockdown epithelial cells or zebrafish embryos are rescued by Verteporfin, a specific inhibitor of YAP transcriptional activity, demonstrating the causative role of YAP dysregulation in the occurrence of these defects. Altogether, this study links NEK8 mutations to dysregulation of the Hippo pathway and provide molecular clues to understand the variability of the multiorgan defects in the patients.
Published: 2016

24. The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Author: Albert David, Chloé Quélin, Clarisse Baumann-Morel, Eric Bieth, Bruno Dumont, Judith Melki, Elise Shaeffer, Yves Alembik, Fabienne Giuliano, Christel Thauvin, Nicolas Chassaing, Sophie Julia, Anne-Lise Delezoide, Marine Lebrun, Tiffany Busa, Geneviève Baujat, David Geneviève, Séverine Audebert, Yline Capri, Patricia Blanchet, Martine Le Merrer, Sandrine Marlin, Mouna Barat-Houari, Marianne Till, Nicole Philip, Laurence Faivre, Patrick Calvas, Karine Nguyen, Alice Masurel, Vidrica Ciorca, François Cartault, Jacqueline Vigneron, Alice Goldenberg, Jelena Martinovic, Monique Mozelle-Nivoix, Renaud Touraine, Ghislaine Plessis, Marie-Line Jacquemont, Jean-Luc Alessandri, Delphine Dupin-Deguine, Valérie Cormier-Daire, Aurélie Fabre, Jeanne Amiel, Marie Brechard, Bertrand Isidor, Salima El Chehadeh, Sylvie Odent, Isabelle Touitou, Josseline Kaplan, Dominique Martin-Coignard, Lucile Pinson, Sabine Sigaudy, Christine Coubes, Didier Lacombe, Frédéric Tm Them, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU La Réunion], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Biologie du Développement, Service de génétique médicale, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital l'Archet, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, 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), 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, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, 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 ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service de Genetique, Service de Génétique Clinique, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CH Le Mans, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, 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 de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), CHU Caen-Hôpital Clémenceau, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: 0301 basic medicine, Proband, Male, Candidate gene, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], Biology, Osteochondrodysplasias, Article, 03 medical and health sciences, symbols.namesake, Kniest dysplasia, Protein Domains, Genetics, medicine, Humans, Connective Tissue Diseases, Collagen Type II, Genetics (clinical), Sanger sequencing, [ SDV ] Life Sciences [q-bio], Arthritis, Collagen Diseases, Retinal Detachment, medicine.disease, Phenotype, Human genetics, 3. Good health, Pedigree, 030104 developmental biology, Amino Acid Substitution, Dysplasia, Spondyloepiphyseal dysplasia congenita, symbols, Female
Abstract: International audience; Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.European Journal of Human Genetics advance online publication, 2 December 2015; doi:10.1038/ejhg.2015.250
Published: 2016

25. Renal cystic dysplasia, paucity of bile ducts, situs inversus, bowing of the femora in two siblings in the Reunion Island: a ciliopathy?

Author: Claire Brayer, Jean-Luc Alessandri, Duksha Ramful, Jean-Pierre Rivière, Marie-Claire Gubler, François Cartault, and Fabrice Cuillier
Subjects: Adult, Male, Fatal outcome, DNA Mutational Analysis, Kinesins, Pathology and Forensic Medicine, Fatal Outcome, Pregnancy, Humans, Medicine, Cilia, Femur, Genetics (clinical), business.industry, Siblings, General Medicine, Anatomy, Kidney Diseases, Cystic, Situs Inversus, medicine.disease, Renal cystic dysplasia, Radiography, Ciliopathy, Situs inversus, Pediatrics, Perinatology and Child Health, Female, Bile Ducts, Bone Diseases, business, Reunion
Published: 2009

26. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium

Author: Ghada A. Otaify, Samia A. Temtamy, Bruno Dallapiccola, Pleasantine Mill, Maria Cristina Digilio, Alessandro De Luca, Laura Vázquez, Victor L. Ruiz-Perez, José A. Caparrós-Martín, Karen E. Heath, Julián Nevado, Judith A. Goodship, Mennat I Mehrez, María Valencia, Pablo Lapunzina, François Cartault, Inmaculada Rueda-Arenas, Mona Aglan, Jean Luc Alessandri, Ministero della Salute, and Ministerio de Economía y Competitividad (España)
Subjects: Ellis-Van Creveld Syndrome, Biology, Receptors, G-Protein-Coupled, Exon, Intraflagellar transport, Genetics, medicine, Humans, Hedgehog Proteins, Exome, Cilia, Molecular Biology, Genetics (clinical), Ellis–van Creveld syndrome, Cells, Cultured, Cilium, Intracellular Signaling Peptides and Proteins, Genetic Variation, Infant, Proteins, Articles, General Medicine, Exons, Fibroblasts, medicine.disease, Phenotype, Smoothened Receptor, Pedigree, Cytoskeletal Proteins, Child, Preschool, RNA splicing, sense organs, Smoothened, Signal Transduction
Abstract: et al., Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35−/− cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1−/−, indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35−/− fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc−/− and Evc2−/− mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia., This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-43365-R) and by funding from the Italian Ministry of Health (RF-2010-2310935, RC-2014 to A.D.L.).
Published: 2015

27. Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Author: Isabelle Coupier, Patrick Edery, Valérie Cormier-Daire, Séverine Audebert-Bellanger, Claire Calmel, Marilyne Le Jule, Fabienne Giuliano, Stanislas Lyonnet, Sophie Blesson, Bérénice Doray, Frédéric Brioude, Clarisse Baumann, Odile Boute, Martin Catala, Jean-Luc Alessandri, Sabine Sigaudy, Fanny Laffargue, Sylvie Odent, Alain Verloes, Lydie Burglen, Didier Lacombe, James Lespinasse, Françoise Praz, Michel Polak, Irène Netchine, Sylvie Rossignol, Bruno Leheup, Géraldine Viot, Yves Le Bouc, Bertrand Isidor, Patricia Blanchet, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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 Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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 ), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pédiatrie et de Génétique Médicale, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital l'Archet, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Les Hôpitaux Universitaires de Strasbourg (HUS), BM1208, Institut National de la Santé Et de la Recherche Médicale, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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 ), Laboratoire de Biologie du Développement ( LBD ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut National de la Santé et de la Recherche Médicale, 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 ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ) -Hôpital Morvan [Brest], Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de neuropédiatrie et pathologie du développement, Service de Génétique Médical, CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], 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), 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), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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 Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]
Subjects: Male, Pathology, medicine.medical_specialty, Beckwith-Wiedemann Syndrome, Genotype, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Beckwith–Wiedemann syndrome, Beckwith–Wiedemann, Biology, 03 medical and health sciences, Genomic Imprinting, Genetics, medicine, Macroglossia, Missense mutation, Humans, Epigenetics, Amino Acid Sequence, Cyclin-Dependent Kinase Inhibitor p57, Genetics (clinical), Alleles, Genetic Association Studies, 030304 developmental biology, Ganglioneuroblastoma, 0303 health sciences, [ SDV ] Life Sciences [q-bio], 030305 genetics & heredity, Cell Cycle, medicine.disease, Phenotype, 3. Good health, Pedigree, CDKN1C, Amino Acid Substitution, Overgrowth syndrome, Mutation, Female, medicine.symptom, imprinting, Sequence Alignment, overgrowth syndrome, Visceromegaly
Abstract: International audience; Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS
Published: 2015

28. Prothrombin Saint-Denis: a natural variant with a point mutation resulting in Asp to Glu substitution at position 552 in prothrombin

Author: Marie-Claude Guillin, Jean-Luc Alessandri, Marie-Dominique Dautzenberg, Dominique Vidaud, Laurence Venisse, Stanislas Rouy, and Annie Bezeaud
Subjects: Male, Parents, chemistry.chemical_classification, Base Sequence, Transition (genetics), Point mutation, Allosteric regulation, Prothrombin level, Infant, Newborn, Mutation, Missense, Hypoprothrombinemias, Hematology, Thromboplastin, Amino acid, Thrombin, chemistry, Biochemistry, medicine, Humans, Point Mutation, Prothrombin, circulatory and respiratory physiology, medicine.drug
Abstract: A new prothrombin variant, with a point mutation at nucleotide 20 029 resulting in Asp 552 to Glu substitution (prothrombin numbering), has been identified in a male newborn. Plasma prothrombin level was
Published: 2006

29. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

Author: Nehla Ghedira, Nathalie Pouvreau, Yline Capri, Odile Fenneteau, Joelle Roume, Aurélie Caye, Bérénice Doray, Laurence Perrin, Odile Boute, Natacha Fillot, Aurélien Trimouille, Cédric Vignal, Yves Alembik, Patricia Blanchet, Valérie Drouin-Garraud, Bertrand Isidor, Marlène Rio, Marion Gérard, Jean-Luc Alessandri, Annick Toutain, Alain Verloes, Albert David, Hélène Cavé, Anne Dieux Coeslier, Clarisse Baumann, Olivier Dulac, Delphine Héron, Sylvie Sauvion, Catherine Vincent-Delorme, Stanislas Lyonnet, Marjorie Willems, Patrice Bouvagnet, and Didier Lacombe
Subjects: 0301 basic medicine, Proband, Adult, Male, medicine.medical_specialty, Adolescent, Cardiomyopathy, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Child, Genetics (clinical), Juvenile myelomonocytic leukemia, business.industry, Noonan Syndrome, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Pedigree, PTPN11, Leukemia, 030104 developmental biology, Phenotype, Leukemia, Myelomonocytic, Juvenile, 030220 oncology & carcinogenesis, Child, Preschool, Speech delay, Immunology, Mutation, ras Proteins, Noonan syndrome, Medical genetics, Female, medicine.symptom, business
Abstract: Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.
Published: 2014

30. Neurocognitive Outcome of Children Exposed to Perinatal Mother-to-Child Chikungunya Virus Infection: The CHIMERE Cohort Study on Reunion Island

Author: Gilles Beullier, Liliane Cotte, Jean-Luc Alessandri, Brahim Boumahni, Isabelle Tiran-Rajaoefera, Alain Fourmaintraux, Irénée Boya, Olivier Rollot, Patrick Gérardin, Magali Carbonnier, Monique Kaminski, Sylvain Samperiz, Marie-Christine Jaffar-Bandjee, Xavier Fritel, Duksha Ramful, Tahir Noormahomed, Alain Michault, François Favier, Jocelyn Okoï, Marc Bintner, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CIC régional épidémiologie clinique/essais cliniques - Ile de la Réunion (CIC-EC), Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunopathology and Infection Research Grouping (IRG), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Centre Hospitalier Gabriel Martin, Centre hospitalier de l'Est Réunion, Saint-Benoît, Clinique Sainte Clotilde, CAMSP La Rose, Clinique Durieux, Le Tampon, La Réunion, Centre hospitalier universitaire de Poitiers (CHU Poitiers), INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UPMC, Gestionnaire, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants, Institut National de la Santé et de la Recherche Médicale (INSERM) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Tenon [APHP] - CHU Cochin [APHP] - Université Paris-Sud - Paris 11 (UP11) - Université Paris Descartes - Paris 5 (UPD5) - Université Pierre et Marie Curie - Paris 6 (UPMC), Service de gynécologie et obstétrique [Poitiers], Université de Poitiers - CHU de Poitiers, CHU de Poitiers, Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de la Réunion - Centre hospitalier Régional Site Félix Guyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), CIC régional épidémiologie clinique/essais cliniques - Ile de la Réunion ( CIC-EC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunopathology and Infection Research Grouping ( IRG ), Université de la Réunion ( UR ) -Centre hospitalier Régional Site Félix Guyon, Centre Hospitalier Gabriel-Martin, CH Gabriel-Martin, Clinique Sainte-Clotilde, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), and INSERM CIC 0802 ( INSERM CIC 0802, CHU de Poitiers )
Subjects: Pediatrics, Viral Diseases, Epidemiology, Developmental Disabilities, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Developmental and Pediatric Neurology, Rate ratio, Diagnostic Radiology, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Child Development, Infectious Diseases of the Nervous System, Pregnancy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Emerging Viral Diseases, Medicine and Health Sciences, Public and Occupational Health, Pregnancy Complications, Infectious, Pediatric Epidemiology, Cognitive Neurology, lcsh:Public aspects of medicine, Radiology and Imaging, Child Health, Gestational age, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Magnetic Resonance Imaging, 3. Good health, [SDV] Life Sciences [q-bio], [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, Neurology, Arboviral Infections, Child, Preschool, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Behavioral and Social Aspects of Health, Chikungunya virus, Cohort study, Research Article, Neglected Tropical Diseases, medicine.medical_specialty, Pediatric Critical Care, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Cognitive Neuroscience, Neuroimaging, Microbiology, Infectious Disease Epidemiology, Cerebral palsy, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Developmental Neuroscience, Diagnostic Medicine, Virology, medicine, Humans, Retrospective Studies, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neonatal encephalopathy, business.industry, Public Health, Environmental and Occupational Health, Infant, Newborn, Biology and Life Sciences, Infant, Retrospective cohort study, lcsh:RA1-1270, medicine.disease, Tropical Diseases, Infectious Disease Transmission, Vertical, Health Care, Small for gestational age, Chikungunya Fever, Neonatology, business, Neurocognitive, Reunion, Viral Transmission and Infection, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Neuroscience
Abstract: Background Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection. Methods The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ≤85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms. Results The mean DQ score was 86.3 (95%CI: 81.0–91.5) in infected children compared to 100.2 (95%CI: 98.0–102.5) in uninfected peers (P, Author Summary Chikungunya virus (CHIKV), an alphaviral infection transmitted by day-biting Aedes mosquitoes, is widespread in Asia and in Africa. Usually, CHIKV causes a self-limiting arthritide, except in debilitated people and in neonates, for whom it can lead to severe disease. Mother-to-child perinatal transmission of CHIKV is a rare event that can occur in the setting of large-scale outbreaks when the risk of maternal viremia at the term of pregnancy becomes non-negligible. In that event, CHIKV can give rise to neonatal infection with a probability of 50%, and prostration and encephalopathy, the two leading clinical pictures in the neonate, represent a continuum in the gradation of an undiscovered central nervous system involvement. We have followed-up 33 children infected at birth between June 2005 and April 2006 on the island of La Réunion, Indian Ocean, and 135 uninfected controls, for assessing their neurodevelopmental performance around the age of two years. Fifty-one percent of infected children had a global neurodevelopmental delay compared to 15% of uninfected peers. Multivariate analysis and neuroradiology suggest without irrefutable evidence a causal relationship between CHIKV infection and neurocognitive outcomes. Our findings suggest that CHIKV infection, acquired in the perinatal period, can cause severe disease with lifelong expected disability.
Published: 2014

31. Fryns syndrome without diaphragmatic hernia, DOOR syndrome or Fryns-like syndrome? Report on patients from Indian Ocean islands

Author: Céline Laurain, Fabrice Cuillier, Duksha Ramful, Laure Jacquemot-Dekkak, Sylvain Samperiz, Marie Kieffer-Traversier, Valérie Malan, Claire Brayer, Jean-Luc Alessandri, Maeva Grondard, Florence Pierre, Isabelle Tiran-Rajaofera, Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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 Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pediatrics, medicine.medical_specialty, Polyhydramnios, Hernia, Hearing Loss, Sensorineural, Rudiger Syndrome, [SDV]Life Sciences [q-bio], Limb Deformities, Congenital, Nails, Malformed, Sensorineural, Craniofacial Abnormalities, Congenital, Fatal Outcome, Fryns syndrome, DOOR syndrome, Indian Ocean Islands, Intellectual Disability, Genetics, medicine, Humans, Diaphragmatic hernia, Hearing Loss, Genetics (clinical), Hernias, Hernia, Diaphragmatic, Comparative Genomic Hybridization, [ SDV ] Life Sciences [q-bio], business.industry, Congenital diaphragmatic hernia, Facies, Infant, Malformed, Microdeletion syndrome, Hand Deformities, medicine.disease, Hypoplasia, Limb Deformities, Phenotype, Nails, Female, Hernias, Diaphragmatic, Congenital, business, Hand Deformities, Congenital, Diaphragmatic
Abstract: International audience; We report on six patients (five unpublished patients) from the Indian Ocean islands, with coarse face, cleft lip or palate, eye anomalies, brachytelephalangy, nail hypoplasia, various malformations (genitourinary or cerebral), abnormal electroencephalograms with impaired neurological examination and lethal outcome. Massive polyhydramnios was noted in the third trimester of pregnancy and neonatal growth was normal or excessive. The combination of the features is consistent with the diagnosis of Fryns syndrome (FS) without congenital diaphragmatic hernia. Besides chromosomal aberrations and microdeletion syndrome, differential diagnoses include conditions overlapping with FS such as Simpson-Golabi-Behmel, and conditions with hypoplasia/absence of the distal phalanges such as DOOR syndrome, Schinzel-Giedion syndrome, and Rudiger syndrome.
Published: 2014

32. Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease

Author: Charles Mccurdy, Lionel Van Maldergem, Helen Cox, Nicola Brunetti-Pierri, Denise Marty, John B. Mulliken, Miriam Erick, Diana Bailey, Joseph Omlor, Ana Tobiasz, Jean Luc Alessandri, Richard M. Pauli, Judith D. Ranells, Helga V. Toriello, Alan Fryer, Angela E. Lin, Amarillis Sanchez-Valle, Helen Murphy, Toriello, Hv, Erick, M, Alessandri, Jl, Bailey, D, BRUNETTI PIERRI, Nicola, Cox, H, Fryer, A, Marty, D, Mccurdy, C, Mulliken, Jb, Murphy, H, Omlor, J, Pauli, Rm, Ranells, Jd, Sanchez Valle, A, Tobiasz, A, Van Maldergem, L, and Lin, Ae
Subjects: Vitamin, Adult, Male, medicine.medical_specialty, Chondrodysplasia Punctata, Adolescent, Physiology, Hyperemesis gravidarum, chemistry.chemical_compound, Crohn Disease, Pregnancy, Internal medicine, Hyperemesis Gravidarum, Vitamin K deficiency, Genetics, Medicine, Humans, Chondrodysplasia punctata, Nasal cartilages, Child, Genetics (clinical), business.industry, Infant, Stippled epiphyses, medicine.disease, Hypoplasia, Fetal Diseases, Endocrinology, chemistry, Child, Preschool, Female, Vitamin K Deficiency, business
Abstract: Chondrodysplasia punctata (CDP) is an etiologically heterogeneous disorder characterized by the radiographic finding of stippled epiphyses (punctate calcifications). It is often accompanied by a characteristic facial appearance, known as the Binder phenotype, which is attributed to hypoplasia of the nasal cartilages; abnormal distal phalanges (brachytelephalangy) are a common component manifestation as well. We report eight patients with a Binder phenotype with or without CDP who all shared a known or suspected maternal deficiency of vitamin K. We suspect that this phenotype is probably under recognized, and we hope to increase awareness about the maternal risk factors, especially hyperemesis gravidarum, which lead to nutritional deficiency.
Published: 2012

33. Congenital heart defects in La Réunion Island: a 6-year survey within a EUROCAT-affiliated congenital anomalies registry

Author: Karim Jamal-Bey, Edouard Kauffmann, Françoise Wuillai, Alain Fourmaintraux, Dominique Caillet, Pierre-Yves Robillard, Fabrice Cuillier, Patrick Gérardin, Yasmina Touret, Claire Bernede-Bauduin, Hélène Bourdial, Jean-Luc Alessandri, Brahim Boumahni, Abdelhafid Edmar, Hanitra Randrianaivo, Annick Laffitte, CHR La réunion, Centre d'Études Périnatales de l'Océan Indien (CEPOI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de gynécologie-obstétrique [La réunion], Groupe Hospitalier Sud-CHR La réunion, Groupe Hospitalier Sud Réunion (GHSR), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, CIC régional épidémiologie clinique/essais cliniques - Ile de la Réunion (CIC-EC), Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation néonatologique et pédiatrique [La Réunion], Service de médecine foetale et foetopathologie, Centre d'Études Périnatales de l'Océan Indien ( CEPOI ), Université de la Réunion ( UR ) -Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Groupe Hospitalier Sud Réunion ( GHSR ), Centre d'Investigation Clinique Regional Epidemiologie Clinique/essais Cliniques - Ile de la Reunion, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Heart Defects, Congenital, Pediatrics, medicine.medical_specialty, Down syndrome, Pregnancy Complications, Cardiovascular, Coarctation of the aorta, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030204 cardiovascular system & hematology, Cardiovascular, Atrial septal defects, 03 medical and health sciences, Congenital, 0302 clinical medicine, Pregnancy, medicine, Prevalence, Humans, Atrioventricular Septal Defect, Registries, Fetal Death, Perinatal Mortality, Heart Defects, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030219 obstetrics & reproductive medicine, business.industry, Infant, Newborn, Infant, General Medicine, medicine.disease, Newborn, 3. Good health, Pregnancy Complications, medicine.anatomical_structure, Ventricle, Pediatrics, Perinatology and Child Health, Pulmonary valve stenosis, Gestation, Female, Cardiology and Cardiovascular Medicine, business, Live Birth, Reunion
Abstract: ObjectivesThis study compares the prevalence and perinatal mortality of congenital heart defects on La Réunion with European (EUROCAT) standards.Methods and resultsData were extracted from a EUROCAT-affiliated congenital malformations registry, covering 88,025 births during the period 2002–2007, on the whole island territory. A total of 512 congenital heart defects were registered, including 424 live births, 18 foetal deaths from 16 weeks of gestation, and 70 terminations of pregnancy. The total prevalence of congenital heart defects was 5.8 per 1000 births and live birth prevalence was 4.8 per 1000. The total prevalence of non-chromosomal congenital heart defects was 5.1 per 1000 births, of which 3% were perinatal deaths, 33.3% prenatally diagnosed, and 11.6% termination of pregnancy. Severe non-chromosomal congenital heart defects – excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis – occurred in 2.1 per 1000 births, of which 10.3% were perinatal deaths, 59.1% prenatally diagnosed, and 24.3% termination of pregnancy. Of the severe congenital heart defects, the rates of single ventricle (0.20‰), Ebstein anomaly (0.11‰), common arterial trunk (0.25‰), and atrioventricular septal defect (0.62‰) exceeded averages found in Europe, although coarctation of the aorta was infrequent. Conversely, rates of ventricular septal defects, atrial septal defects, and pulmonary valve stenosis were inferior to European standards. Slightly less than half of the congenital heart defects of chromosomal origin were associated with Down syndrome.ConclusionIn La Réunion, the total prevalence of congenital heart defects is far inferior to that found in Europe. The difference can be attributable to lower prevalences of mild congenital heart defects.
Published: 2012

34. Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

Author: Maria Belar Ortega, Laurent Daniel, Rosário Stone, Nicole Laurent, Jonathan A. Bernstein, Nicolas Chassaing, Damien Brackman, Ralph J. DeBerardinis, Audrey Pawtowski, Christelle Thauvin, Marie Christine Machet, Deborah Bartholdi, John Tolmie, Fabienne Prieur, Annie Michaud, Katherine Lachlan, Philippe Labrune, Dominique Bonneau, Carola Saloranta, Clarisse Baumann, Marie Claire Gubler, Sui Yu, Jean Pierre Rivière, Amir Peleg, Jean Luc Alessandri, Alix Clemenson, Géraldine Viot, Carol L. Clericuzio, Nicole Picard, Satu-Leena Sallinen, Anne Lise Delezoide, Martin Bitzan, Nancy Braverman, Sophie Blesson, Chantal Loirat, Christelle Arrondel, Helen V. Firth, Harald Gaspar, Julia Tantau, Albert David, Silvia Majore, Annie Levy-Mozziconacci, Stéphane Triau, François Cartault, Corinne Antignac, Olivier Gribouval, Vincent Morinière, Diana Wellesley, Bérénice Doray, Pierre Corvol, Sylvie Cloarec, Julian R. Sampson, David Chitayat, Lotte Nylandsted Krogh, Ahmed Alfares, University of Zurich, and Gribouval, Olivier
Subjects: medicine.medical_specialty, 2716 Genetics (clinical), 10039 Institute of Medical Genetics, Angiotensinogen, 030232 urology & nephrology, Genes, Recessive, Prenatal diagnosis, 610 Medicine & health, Peptidyl-Dipeptidase A, Biology, medicine.disease_cause, Receptor, Angiotensin, Type 1, Kidney Tubules, Proximal, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, 1311 Genetics, Internal medicine, Renin, Renin–angiotensin system, Genetics, medicine, Animals, Humans, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Kidney, Mutation, Angiotensin II receptor type 1, medicine.disease, 3. Good health, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Urogenital Abnormalities, Renal blood flow, 570 Life sciences, biology, Anuria, medicine.symptom, Potter sequence
Abstract: Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
Published: 2012

35. Pre- and postnatal phenotype of 6p25 deletions involving the FOXC1 gene

Author: Marion Gérard, Julien Boumendil, Anne-Lise Delezoide, Eva Pipiras, Alain Verloes, Brigitte Benzacken, Suonavy Khung-Savatovsky, Chan Huel, Pierre Bitoun, Fabien Guimiot, Stéphane Serero, Jean-Luc Alessandri, Jacques Elion, Romain Guilherme, Andrée Delahaye, Séverine Drunat, Pierre Gressens, Azzedine Aboura, and Stéphanie Robin
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Biology, Dysgenesis, Fetus, Dandy–Walker syndrome, Anterior Eye Segment, Cerebellar Diseases, Pregnancy, Gene duplication, Genetics, medicine, Humans, Eye Abnormalities, Gene, Genetics (clinical), In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, Breakpoint, Eye Diseases, Hereditary, Forkhead Transcription Factors, medicine.disease, Phenotype, eye diseases, Child, Preschool, Chromosomes, Human, Pair 6, Female, sense organs, Haploinsufficiency, Dandy-Walker Syndrome, Gene Deletion, Comparative genomic hybridization
Abstract: FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation.
Published: 2011

36. RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome

Author: Jean-Luc Alessandri, Valérie Cormier-Daire, Nathalie Dagoneau, Jean-Marc Laville, Jean-Christophe Hébert, and Julien Baruteau
Subjects: Male, DNA Mutational Analysis, Molecular Sequence Data, Biology, Comoros, Genu Valgum, Craniosynostosis, Pregnancy, Chromosome Segregation, Genetics, medicine, Humans, Abnormalities, Multiple, Family, Syndactyly, Child, Genetics (clinical), Base Sequence, Brachydactyly, Preaxial polydactyly, Infant, Newborn, Infant, Anatomy, Syndrome, medicine.disease, Carpenter syndrome, Pedigree, Radiography, Haplotypes, Polysyndactyly, rab GTP-Binding Proteins, Agenesis, Child, Preschool, Mutation, Female
Abstract: We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in four relatives of Comorian origin with Carpenter syndrome. All children presented with acrocephaly and polysyndactyly. However, intrafamilial variability was observed with variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge. All children also presented with a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly (2/4) in the hands, and preaxial polydactyly (3) and syndactyly (4) in the toes. Mental development was normal in all four children but the eldest one presented with impaired motor development as a result of orthopedic complications. Brain imaging showed hydrocephalus in 2/4 and additional features included genu valgum (2/4), abnormal genitalia (3/4), corneal anomaly (2/4), umbilical hernia (1/4), severe cyphoscoliosis (1), patent ductus arteriosus (1/4), and accessory spleen (1). In contrast to previous reports, growth was below average except for one patient and the eldest one became moderately overweight with time. We conclude from the report of this large unique family with four affected children that Carpenter syndrome is a genetically homogenous but a clinically variable condition.
Published: 2010

37. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency

Author: Duksha Ramful, Fabrice Cuillier, Jean-Luc Alessandri, Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), and Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion]
Subjects: medicine.medical_specialty, Chondrodysplasia Punctata, [SDV]Life Sciences [q-bio], Pathology and Forensic Medicine, 03 medical and health sciences, Congenital, Young Adult, Pregnancy, Internal medicine, Vitamin K deficiency, Medicine, Humans, Chondrodysplasia punctata, Brachytelephalangic Chondrodysplasia Punctata, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, 030305 genetics & heredity, Infant, Newborn, Infant, General Medicine, Hand Deformities, medicine.disease, Newborn, Phenotype, 3. Good health, Radiography, Pregnancy Complications, Endocrinology, K deficiency, Pediatrics, Perinatology and Child Health, Female, Vitamin K Deficiency, Anatomy, business, Hand Deformities, Congenital, Maternal vitamin
Abstract: International audience; no abstract
Published: 2010

38. Severe bullous skin lesions associated with Chikungunya virus infection in small infants

Author: Stéphanie Robin, Léon Benhamou, Jacques Marichy, Marie-Christine Jaffar-Bandjee, Khaled Ezzedine, Julie Zettor, Duksha Ramful, Jean-Luc Alessandri, and Jean-Pierre Rivière
Subjects: Male, medicine.medical_specialty, Pathology, Biopsy, Enzyme-Linked Immunosorbent Assay, Antibodies, Viral, medicine.disease_cause, Polymerase Chain Reaction, Diagnosis, Differential, Epidemiology, Humans, Immunologic Factors, Medicine, Chikungunya, Alphavirus infection, skin and connective tissue diseases, Retrospective Studies, Skin, Skin Diseases, Vesiculobullous, integumentary system, Alphavirus Infections, business.industry, Infant, Newborn, Immunoglobulins, Intravenous, Infant, Retrospective cohort study, Viral Load, medicine.disease, Dermatology, Treatment Outcome, DNA, Viral, Pediatrics, Perinatology and Child Health, Female, Viral disease, Differential diagnosis, business, Chikungunya virus, Total body surface area, Viral load, Follow-Up Studies
Abstract: The aim of this study was to describe a pediatric case series of Chikungunya infection associated with extensive bullous skin lesions, a severe and unknown form of the disease, during the 2005-2006 outbreak in La Réunion Island.Retrospective descriptive hospital-based study in children presenting blistersor = 10% of total body surface area with laboratory-confirmed Chikungunya infection.Eight boys and five girls with a mean age of 3.4 months were included. Blistering began after an average of 2 days after onset of fever and affected 21.5% (10% to 35%) of the total body surface area. Reverse transcription-polymerase chain reaction of blister fluid (n = 5) was positive with a mean viral load sometimes higher than in concurrent serum. Histopathologic examination (n = 10) showed intraepidermal blisters. Hospitalization and repeated dressing changes under general anesthesia were required. No death occurred. On follow-up, long term repigmentation was excellent with sometimes cosmetic sequelae.Chikungunya should be included in the differential diagnosis of febrile blistering dermatoses in small infants in epidemic areas.
Published: 2009

39. Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus

Author: Jean Luc Alessandri, Pascale Krejbich Trotot, Marie Christine Jaffar-Bandjee, Duksha Ramful, Pascale Guiraud, Renubala Sahoo, Melanie Denizot, Bernard Alex Gaüzère, Philippe Gasque, Ghislaine Lee-Pat-Yuen, Trina Das, Jean Jacques Hoarau, Stéphanie Robin, Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Réanimation Néonatale et Pédiatrique, and CHD Félix Guyon
Subjects: [SDV]Life Sciences [q-bio], 030231 tropical medicine, Neuroinfection, Biology, medicine.disease_cause, Communicable Diseases, Arbovirus, Communicable Diseases, Emerging, 03 medical and health sciences, 0302 clinical medicine, medicine, alphavirus, Animals, Humans, Chikungunya, Neurodegeneration, Alphavirus infection, innate immunity, 030304 developmental biology, Emerging, Aedes, 0303 health sciences, Alphavirus Infections, General Neuroscience, virus diseases, Tropical disease, Outbreak, Meningoencephalitis, medicine.disease, biology.organism_classification, Virology, 3. Good health, Immunology, Central Nervous System Viral Diseases, Chikungunya virus, Encephalitis
Abstract: International audience; Chikungunya virus (CHIKV) is transmitted by Aedes mosquitoes and causes an acute symptomatic illness with fever, skin rash, and incapacitating arthralgia, which can evolve into chronic rheumatoid arthritis in elderly patients. This is a tropical disease originally described in central/east Africa in the 1960s, but its 2004 re-emergence in Africa and rapid spread in lands in and around the Indian Ocean (Reunion island, India, Malaysia) as well as Europe (Italy) led to almost 6 million cases worldwide. The risk of importation and spreading diseases with long-term sequelae is even greater today given the global distribution of the vectors (including in the Americas), increased tourism and the apparent capacity of CHIKV to produce high levels of viremia (10(9)-10(12) virus/ml of blood) and new mutants. CHIKV-associated neuropathology was described early in the 1960s, but it is the unprecedented incidence rate in Indian Ocean areas with efficient clinical facilities that allowed a better description of cases with severe encephalitis, meningoencephalitis, peripheral neuropathies and deaths among newborns (mother-to-child infection), infants and elderly patients. Death rates following CHIKV infection were estimated at 1:1000 cases in la Reunion's outbreak. These clinical observations have been corroborated by experimental infection in several mouse models, leading to CNS pathologies. We further describe in this review the capacity of CHIKV to infect neurons and glial cells, delineate the fundamental innate (intrinsic) immune defence mechanisms to protect from infection and argue about the possible mechanisms involved in the encephalopathy.
Published: 2009

40. Perlman syndrome: report, prenatal findings and review

Author: Duksha Ramful, Stéphanie Robin, Jean-Pierre Rivière, Sandrine Ernould, Fabrice Cuillier, Jean-Luc Alessandri, Stefan de Napoli-Cocci, and Sylvie Rossignol
Subjects: Polyhydramnios, medicine.medical_specialty, Pediatrics, Prenatal diagnosis, Consanguinity, Kidney, Wilms Tumor, Ultrasonography, Prenatal, Fetal Macrosomia, Fatal Outcome, Pregnancy, Internal medicine, Prenatal Diagnosis, Genetics, medicine, Fetal macrosomia, Humans, Genetic Predisposition to Disease, Perlman syndrome, Genetics (clinical), business.industry, Infant, Newborn, Wilms' tumor, Syndrome, medicine.disease, Amniotic Fluid, Endocrinology, Overgrowth syndrome, Nephromegaly, Female, medicine.symptom, business
Abstract: Perlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios with neonatal macrosomia, nephromegaly, distinctive facial appearance, renal dysplasia, nephro-blastomatosis, and predisposition to Wilms tumor (WT). We report on a newborn with prenatal sonographic signs of Perlman syndrome, large fetal ascites, nephromegaly and macrosomia. The clinical course was marked by neonatal distress, renal failure and refractory hypoxemia leading to death at 2 days of life. Renal histologic examination showed bilateral nephroblastomatosis. Genetic or epigenetic alterations of the 11p15 region (involved in the BWS), including mutation of the CDKN1C gene were excluded. No mutation of the GPC3 gene was identified. We review the 28 patients who have been reported with Perlman syndrome. The prognosis of Perlman syndrome is poor with a high neonatal mortality rate. Among the infants who survived beyond the neonatal period, 64% developed a WT and all had a developmental delay. Fetal macrosomia, ascites and polyhydramnios are frequent manifestations. Clinical overlaps with other overgrowth syndromes particularly Beckwith-Wiedemann syndrome and Simpson-Golabi-Behmel syndrome have been emphasized. Perlman syndrome is considered as an autosomal recessive condition. We review 19 patients from seven sibships with parental consanguinity in two families only. The other cases were sporadic. The 28 reported patients had only 10 unaffected sibs. The low percentage of consanguinity among parents is also puzzling for a rare recessive condition. The molecular basis of Perlman syndrome is unknown. (Epi)genetic anomalies of 11p15 and mutations in GPC3 were not studied in most of the previous reports.
Published: 2008

41. Neurologic manifestations of pediatric chikungunya infection

Author: Gérald Rigou, Duksha Ramful, Jean-Luc Alessandri, Florence Le Seach, Stéphanie Robin, and Marie-Christine Jaffar-Bandjee
Subjects: Male, Pathology, medicine.medical_specialty, Pediatrics, Adolescent, Disease, Electroencephalography, medicine.disease_cause, Cerebrospinal fluid, Indian Ocean Islands, medicine, Humans, Neurologic sequelae, Chikungunya, Age of Onset, Child, Pathological, Retrospective Studies, medicine.diagnostic_test, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Age Factors, Encephalitis, Arbovirus, Headache, Infant, Newborn, Brain, Infant, medicine.disease, Echoencephalography, Magnetic Resonance Imaging, Meningitis, Viral, Child, Preschool, Pediatrics, Perinatology and Child Health, Acute disseminated encephalomyelitis, Consciousness Disorders, RNA, Viral, Female, Neurology (clinical), business, Chikungunya virus, Encephalitis
Abstract: Chikungunya virus, a mosquito-borne arbovirus, was responsible for a massive epidemic in La Réunion Island during 2005 to 2006. The disease is usually benign, but neurologic involvement, with sometimes fatal outcome, has been described. We report a retrospective hospital-based pediatric series of 30 children (23 boys and 7 girls) who presented neurologic manifestations of chikungunya such as encephalitis (n = 12), febrile seizures (n = 10), meningeal syndrome (n = 4), and acute encephalopathy (n = 4). Cerebrospinal fluid biological and cytological analyses (n = 23) were unremarkable except for 1 case of acute disseminated encephalomyelitis. The presence of viral genome in cerebrospinal fluid was inconstantly positive. Brain magnetic resonance imaging (MRI) scans (n = 14) were abnormal in 5 cases. Electroencephalography was nonspecific. Two patients died. At discharge and 6 months later, 5 children had neurologic sequelae. Patients with initial severe neurologic presentation and having pathological brain MRI had more sequelae or fatal disease.
Published: 2008

42. Crouzon syndrome and Bent bone dysplasia associated with mutations at the same Tyr-381 residue inFGFR2gene

Author: Valérie Cormier Daire, F. Di Rocco, Eric Arnaud, Corinne Collet, Jean-Luc Alessandri, and M. Balu
Subjects: Mutation, business.industry, Crouzon syndrome, medicine.disease, medicine.disease_cause, Molecular biology, Residue (chemistry), Developmental genetics, Bent bone dysplasia, Genetics, medicine, Missense mutation, Craniofacial dysostosis, business, Gene, Genetics (clinical)
Published: 2013

43. Congenital Syphilis, Réunion Island, 2010

Author: Emilie Boidin Lespine, Anne Gallay, Véronique Goulet, Eric D'Ortenzio, Jean-Luc Alessandri, Marc Bertsch, Juliana Ramiandrisoa, Lydéric Aubert, Pierre-Yves Robillard, Institut de Veille Sanitaire (INVS), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Groupe de Recherche en Immunopathologies et maladies infectueuses ( GRI ), and Université de la Réunion ( UR ) -Centre hospitalier Régional Site Félix Guyon
Subjects: mass screening, Pediatrics, medicine.medical_specialty, Population, Réunion Island, letter, syphilis, lcsh:Medicine, Men who have sex with men, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, Treponema pallidum, Seroconversion, Letters to the Editor, bacteria, education, Indian Ocean, Mass screening, Retrospective Studies, Pregnancy, education.field_of_study, 030219 obstetrics & reproductive medicine, business.industry, Incidence, Syphilis, Congenital, Incidence (epidemiology), lcsh:R, congenital, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.disease, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Congenital syphilis, Syphilis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, pregnancy, business, Reunion
Abstract: To the Editor: Syphilis, caused by the bacterium Treponema pallidum, is primarily a sexually transmitted infection, but T. pallidum can also be transmitted by infected pregnant women to their children. Every year, at least 500,000 children are born with congenital syphilis (CS); maternal syphilis causes another half million stillbirths and abortions, usually in countries with limited resources (1). However, CS has been recently found in industrialized countries such as the United States, where the CS rate increased by 23% during 2005–2008, after a 38% increase in the syphilis rate among US women and girls during an earlier period (2004–2007) (2). Reunion Island, a French overseas territory with 810,000 inhabitants, has a health care system similar to that in continental France. Neither syphilis infection, CS, nor other trepanomatosis (yaws) is notifiable. Since 2006, an increase in early syphilis was documented, first in men who have sex with men infected with HIV and second in the general population. In 2009, we conducted a retrospective study by using data from 2004–2009 to document the situation of CS on the island. Data from all public (n = 4) and private (n = 2) hospitals on the island with neonatology and obstetrical departments were investigated. Birth deliveries at home were not included. Inclusion criteria were positive specific (T. pallidum hemagglutination assay) and nonspecific (Venereal Disease Research Laboratory [VDRL]) test results for Treponema spp. among children
Published: 2011

44. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes

Author: Georges Deschênes, Arnold Köckerling, Henny H. Lemmink, Willy M. Nillesen, Lisa M. Guay-Woodford, Dorthe K. Zimmermann, Lothar Károlyi, Christian Wieg, Lambertus P. van den Heuvel, Corinne Antignac, Karl-Heinz Grzeschik, Louis David, Christopher J. Wright, Pascal Saunier, Michele Deschaux, R. Vargas, Friedhelm Hildebrandt, Hannsjörg W. Seyberth, Andreas Ziegler, Nine V A M Knoers, Matthias Brandis, Lionel Forestier, Willem Proesmans, Emmanuel Cougoureux, Jean-Luc Alessandri, Steven C. Hebert, Manuela C. Koch, Martin Konrad, Delphine Feldmann, Gian Franco Rizzoni, Leo A. H. Monnens, Geneviève Jean, Gilbert Madrigal, Niaudet P, Frederique Lorridon, Martin Vollmer, and Bernd Roth
Subjects: medicine.medical_specialty, Potassium Channels, Genotype, DNA Mutational Analysis, Molecular Sequence Data, medicine.disease_cause, Bartter syndrome, Genetic Heterogeneity, Internal medicine, Genetics, medicine, Humans, Amino Acid Sequence, Potassium Channels, Inwardly Rectifying, Molecular Biology, Genetics (clinical), Mutation, CLCNKB, Kidney, biology, Genetic heterogeneity, Bartter Syndrome, Genetic Variation, General Medicine, medicine.disease, Potassium channel, Bartter's syndrome, medicine.anatomical_structure, Endocrinology, Genes, biology.protein, ROMK
Abstract: Inherited renal tubular disorders associated with hypokalemic alkalosis (Bartter-like syndromes) can be subdivided into at least three clinical phenotypes: (i) the hypocalciuric-hypomagnesemic Gitelman variant; (ii) the classic variant; and (iii) the antenatal hypercalciuric variant (also termed hyperprostaglandin E syndrome). Mutations in the Na-Cl cotransporter (NCCT) underlie the pathogenesis of the Gitelman variant and mutations in the Na-K-2Cl cotransporter (NKCC2) have recently been identified in the antenatal hypercalciuric variant. We now describe mutations in the gene encoding the inwardly-rectifying potassium channel, ROMK, in eight kindreds with the antenatal variant of Bartter syndrome. These findings indicate that antenatal Bartter syndrome is genetically heterogeneous and provide new insights into the molecular pathogenesis of Bartter-like syndromes.
Published: 1997

45. T-cell lymphoma and pigtail catheter drainage of a massive paraneoplastic pleuro-pericardial effusion in a child

Author: Jean-Luc Alessandri, Samuel Vernaz, and Alban-Elouen Baruteau
Subjects: Male, Tachycardia, Cardiac Catheterization, medicine.medical_specialty, Paraneoplastic Syndromes, Pleural effusion, Physical examination, Lymphoma, T-Cell, Pericardial Effusion, Humans, Medicine, T-cell lymphoma, cardiovascular diseases, Derivation, Child, Lung, medicine.diagnostic_test, business.industry, medicine.disease, Cardiac Tamponade, Surgery, Catheter, medicine.anatomical_structure, Effusion, Echocardiography, cardiovascular system, Drainage, medicine.symptom, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business
Abstract: An 9-year-old black African boy was admitted for tachypnoea. His medical history was free of event. Clinical examination revealed abolition of vesicular murmure in the right lung, tachycardia, and mild jugular venous distension. Chest X-ray showed complete opacification of the right hemithorax due to massive pleural effusion. Pigtail catheter drainage yielded …
Published: 2009

46. 16 Épidémie d’infections nosocomiales à pseudomonas pickettii dans une unité de réanimation néonatale à partir d’incubateurs

Author: Claire, Brayer, primary, Laurence, Dupuy, additional, Duk, Ramful, additional, Sylvain, Sampériz, additional, Henry, Pilorget, additional, Isabelle, Rajaofera, additional, Tania, Attali, additional, and Jean-Luc, Alessandri, additional
Published: 2005
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