Search

Your search keyword '"Sarah Grotto"' showing total 23 results
Start Over Author "Sarah Grotto"
23 results on '"Sarah Grotto"'

1. Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders

Author

Maude Grelet, Véronique Blanck, Sabine Sigaudy, Nicole Philip, Fabienne Giuliano, Khaoula Khachnaoui, Godelieve Morel, Sarah Grotto, Julia Sophie, Céline Poirsier, James Lespinasse, Laurent Alric, Patrick Calvas, Gihane Chalhoub, Valérie Layet, Arnaud Molin, Cindy Colson, Luisa Marsili, Patrick Edery, Nicolas Lévy, and Annachiara De Sandre-Giovannoli

Subjects
Progeroid, Panel, Pathogenic,variant, Medicine
Abstract

Abstract Background Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. Methods Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. Results Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives. Conclusions High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms (“Medicine France Genomics 2025” Plan), in families without molecular diagnosis.

Published
2019
Full Text
View/download PDF

2. Two novel variations p.( <scp>Ser1275Thr</scp> ) and p.( <scp>Ser1275Arg</scp> ) in <scp> FLT4 </scp> causing prenatal hereditary lymphedema type 1

Author

Yosra Lajmi, Laurence Loeuillet, Giulia Petrilli, Charles Egloff, Juliette Nectoux, Clémence Molac, Nathalie Roux, Emmanuelle Pannier, Amale Achaiaa, Zaina Ait Arkoub, Sophie Chuon, Aurélie Coussement, Jean Michel Dupont, Valérie Malan, Emmanuel Spaggiari, Ferechte Razavi, Jeanne Amiel, Bettina Bessières, Sarah Grotto, and Tania Attié‐Bitach

Subjects
Embryology, Health, Toxicology and Mutagenesis, Pediatrics, Perinatology and Child Health, Toxicology, Developmental Biology
Published
2022
Full Text
View/download PDF

3. Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect

Author

Lucile Boutaud, Benedetta Ruzzenente, Aude Tessier, Olivia Anselem, Emmanuelle Pannier, Sarah Grotto, Naïma Talhi, Daniel Amram, Marjolaine Willems, Constance Wells, Patricia Blanchet, Yuri Musizzano, Clémence Jauny, Patrick Nitschke, Christine Bole-Feysot, Bettina Bessières, Houria Salhi, Amale Achaiaa, Metodi D Metodiev, Ferechte Razavi, Agnès Rötig, Laurence Loeuilllet, and Tania Attié-Bitach

Subjects
Neurology (clinical)
Abstract

Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity. Here, we report a detailed pathological and neuro-histopathological investigation of nine foetuses from four unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in three different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a Complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit; and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis. We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counselling should be considered.

Published
2022
Full Text
View/download PDF

4. Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Author

Daphné Lehalle, Ange‐Line Bruel, Antonio Vitobello, Anne‐Sophie Denommé‐Pichon, Yannis Duffourd, Mirna Assoum, Jeanne Amiel, Geneviève Baujat, Bettina Bessieres, Stefania Bigoni, Lydie Burglen, Guillaume Captier, Rodolphe Dard, Patrick Edery, Fernanda Fortunato, David Geneviève, Alice Goldenberg, Laurent Guibaud, Delphine Héron, Muriel Holder‐Espinasse, Damien Lederer, Fermina Lopez Grondona, Sarah Grotto, Sandrine Marlin, Gwenaël Nadeau, Arnaud Picard, Massimiliano Rossi, Joëlle Roume, Damien Sanlaville, Pascale Saugier‐Veber, Stéphane Triau, Maria Irene Valenzuela Palafoll, Clémence Vanlerberghe, Lionel Van Maldergem, Myriam Vezain, Catherine Vincent‐Delorme, Einat Zivi, Julien Thevenon, Pierre Vabres, Christel Thauvin‐Robinet, Patrick Callier, and Laurence Faivre

Subjects
Eye Diseases, Cleft Lip, Neurocutaneous Syndromes, Skin Diseases, Spine, Coloboma, Craniofacial Abnormalities, Diagnosis, Differential, Nasal Polyps, Face, Genetics, Humans, Lipomatosis, Eye Abnormalities, Lipoma, Agenesis of Corpus Callosum, Ear, External, Respiratory System Abnormalities, Genetics (clinical)
Abstract

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

Published
2022
Full Text
View/download PDF

5. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish

Author

Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, Marion Delous, 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), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Genève = University of Geneva (UNIGE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Morvan [Brest], CH Morlaix, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Louis Mourier - AP-HP [Colombes], Université de Lyon, 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 ), CHU Pontchaillou [Rennes], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hôpital Robert Debré, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by CNRS, Inserm, Université de Montpellier, Université Paris 7 and Université Lyon 1 through recurrent funding, the Fondation Maladies Rares ('Small Animal Models and Rare Diseases' program, no. 20161207), the Agence Nationale de la Recherche (no. ANR-18CE12-0007-01), and the Fondation pour la recherche sur le Cerveau « Espoir en tête » (confocal microscope). E.B. was supported by an European Molecular Biology Organization long-term fellowship (ALTF-284-2019) and the Novartis Foundation for medical-biological Research (18B112)., and ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018)

Subjects
minor introns, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, MESH: Humans, MESH: Mutation, MESH: Fetal Growth Retardation, MESH: RNA, Small Nuclear, U4atac, splicing, genetic disease, MESH: Ciliopathies, MESH: Animals, MESH: Zebrafish, MESH: Female, MESH: Spliceosomes, primary cilium
Abstract

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Published
2023
Full Text
View/download PDF

6. Noninvasive Prenatal Diagnosis of a Paternally Inherited MEN1 Pathogenic Splicing Variant

Author

Thomas Huby, Edouard Le Guillou, Cyril Burin des Roziers, Laurence Pacot, Audrey Briand-Suleau, Albain Chansavang, Aurélie Toussaint, Véronique Duchossoy, Nicolas Vaucouleur, Virginie Benoit, Laurence Lodé, Clémence Molac, Marie-Odile North, Sarah Grotto, Vassilis Tsatsaris, Anne Jouinot, Béatrix Cochand-Priollet, Anne-Cécile Paepegaey, Juliette Nectoux, Lionel Groussin, and Eric Pasmant

Subjects
Adult, Male, endocrine system diseases, Hyperparathyroidism, Noninvasive Prenatal Testing, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Biochemistry, Endocrinology, Pregnancy, Multiple Endocrine Neoplasia Type 1, Paternal Inheritance, Humans, Female, Genetic Testing
Abstract

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1. The uncertainty of pathogenicity of MEN1 variants complexifies the selection of the patients likely to benefit from specific care. Objective MEN1-mutated patients should be offered tailored tumor screening and genetic counseling. We present a patient with hyperparathyroidism for whom genetic analysis identified a variant of uncertain significance in the MEN1 gene (NM_130799.2): c.654G > T p.(Arg218=). Additional functional genetic tests were performed to classify the variant as pathogenic and allowed prenatal testing. Design Targeted next generation sequencing identified a synonymous variant in the MEN1 gene in a 26-year-old male with symptomatic primary hyperparathyroidism. In silico and in vitro genetic tests were performed to assess variant pathogenicity. Results Genetic testing of the proband’s unaffected parents showed the variant occurred de novo. Transcript study showed a splicing defect leading to an in-frame deletion. The classification of the MEN1 variant as pathogenic confirmed the diagnosis of MEN1 and recommended an adapted medical care and follow-up. Pathogenic classification also allowed to propose a genetic counseling to the proband and his wife. Noninvasive prenatal diagnosis was performed with a personalized medicine-based protocol by detection of the paternally inherited variant in maternal plasmatic cell free DNA, using digital PCR. Conclusion We showed that functional genetic analysis can help to assess the pathogenicity of a MEN1 variant with crucial consequences for medical care and genetic counseling decisions.

Published
2021
Full Text
View/download PDF

7. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Newell Belnap, Bert B.A. de Vries, Austin Larson, Rolph Pfundt, Marijke R. Wevers, Valérie Benoit, Markus Zweier, Pascal Joset, Anita Rauch, Angela Bahr, Jeroen Mourmans, Patricia G Wheeler, Or Gozani, Marisa V. Andrews, Monica H. Wojcik, Didier Lacombe, Sarah Grotto, Marwan Shinawi, Lot Snijders Blok, Conny M. A. van Ravenswaaij-Arts, Keri Ramsey, Deepanwita Sengupta, Mariarosaria Lang-Muritano, Isabelle Maystadt, Katharina Steindl, Paolo Zanoni, Antonio Vitobello, Geoffroy Delplancq, Katrin Õunap, Tania Attié-Bitach, Heinrich Sticht, Giulia Petrilli, Laurence Faivre, Vassilis Tsatsaris, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
0301 basic medicine, In silico, Biology, Article, REGION, 03 medical and health sciences, ROGERS-DANKS-SYNDROME, 0302 clinical medicine, Missense mutation, HISTONE H3, Gene, Genetics (clinical), Loss function, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DELETION, DEFECTS, Methylation, Phenotype, LYSINE 36, 030104 developmental biology, Molecular mechanism, WOLF-HIRSCHHORN-SYNDROME, 030217 neurology & neurosurgery, Function (biology), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype., Genetics in Medicine, 23 (8)

Published
2021
Full Text
View/download PDF

8. Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy

Author

Estelle Gandjbakhch, Pascale Richard, Céline Bordet, Laurent Martin, Sarah Grotto, Philippe Charron, Yves Alembik, Véronique Fressart, Hervé Gorka, Paul Fornes, Geoffroy Lorin de la Grandmaison, Caroline Rambaud, Gilles Millat, Isabelle Marey, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Hôpital Raymond Poincaré [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital de Hautepierre [Strasbourg], Hospices Civils de Lyon (HCL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
0301 basic medicine, medicine.medical_specialty, Cardiomyopathy, sudden death, Autopsy, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030204 cardiovascular system & hematology, 030105 genetics & heredity, Sudden death, genetic testing, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, post-mortem, Genetic testing, cardiac death, medicine.diagnostic_test, biology, business.industry, Conventional autopsy, De novo mutation, General Medicine, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Transthyretin, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Medicine, business, cardiomyopathy, Research Article
Abstract

Post-mortem genetic analyses may help to elucidate the cause of cardiac death. The added value is however unclear when a cardiac disease is already suspected or affirmed. Our aim was to study the feasibility and medical impact of post-mortem genetic analyses in suspected cardiomyopathy. We studied 35 patients with cardiac death and suspected cardiomyopathy based on autopsy or clinical data. After targeted sequencing, we identified 15 causal variants in 15 patients (yield 43%) in sarcomeric (n = 8), desmosomal (n = 3), lamin A/C (n = 3) and transthyretin (n = 1) genes. The results had various impacts on families, i.e. allowed predictive genetic testing in relatives (15 families), planned early therapeutics based on the specific underlying gene (5 families), rectified the suspected cardiomyopathy subtype (2 families), assessed the genetic origin of cardiomyopathy that usually has an acquired cause (1 family), assessed the diagnosis in a patient with uncertain borderline cardiomyopathy (1 family), reassured the siblings because of a de novo mutation (2 families) and allowed prenatal testing (1 family). Our findings suggest that post-mortem molecular testing should be included in the strategy of family care after cardiac death and suspected cardiomyopathy, since genetic findings provide additional information useful for relatives, which are beyond conventional autopsy.

Published
2020
Full Text
View/download PDF

9. Clinical and functional heterogeneity associated with the disruption of Retinoic Acid Receptor beta

Author

Véronique Caron, Nicolas Chassaing, Nicola Ragge, Felix Boschann, Angelina My-Hoa Ngu, Elisabeth Meloche, Sarah Chorfi, Saquib A. Lakhani, Weizhen Ji, Laurie Steiner, Julien Marcadier, Philip R. Jansen, Laura A. van de Pol, Johanna M. van Hagen, Alvaro Serrano Russi, Gwenaël Le Guyader, Magnus Nordenskjöld, Ann Nordgren, Britt-Marie Anderlid, Julie Plaisancié, Corinna Stoltenburg, Denise Horn, Anne Drenckhahn, Fadi F. Hamdan, Mathilde Lefebvre, Tania Attie-Bitach, Peggy Forey, Vasily Smirnov, Françoise Ernould, Marie-Line Jacquemont, Sarah Grotto, Alberto Alcantud, Alicia Coret, Rosario Ferrer-Avargues, Siddharth Srivastava, Catherine Vincent-Delorme, Shelby Romoser, Nicole Safina, Dimah Saade, James R. Lupski, Daniel G. Calame, David Geneviève, Nicolas Chatron, Caroline Schluth-Bolard, Kenneth A. Myers, William B. Dobyns, Patrick Calvas, Caroline Salmon, Richard Holt, Frances Elmslie, Marc Allaire, Daniil M. Prigozhin, André Tremblay, Jacques L. Michaud, Pediatrics, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
Genetics (clinical)
Abstract

Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Published
2023
Full Text
View/download PDF

11. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author

Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta

Subjects
musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Published
2022

12. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects

Author

Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Sarah Grotto, Lyse Ruaud, Caroline Michot, Martin Castelle, Agnès Guët, Laurent Guibaud, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Tania Attié-Bitach, Patrick Edery, Sylvie Mazoyer, and Marion Delous

Abstract

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene,RNU4ATAC, has been found mutated in Taybi-Linder (MOPD1/TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Here, we report a homozygousRNU4ATACmutation in the Stem II domain, n.16G>A, in two unrelated patients presenting with both typical traits of the Joubert syndrome (JBTS), a well-characterized ciliopathy, and of TALS/RFMN/LWS, thus widening the clinical spectrum ofRNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. This finding is supported by alterations of primary cilium function in TALS and JBTS/RFMN fibroblasts, as well as byu4ataczebrafish model, which exhibit ciliopathy-related phenotypes and ciliary defects. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Published
2021
Full Text
View/download PDF

13. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Author

Yannis Duffourd, Catherine Sarret, B. Catteau, Rachel G. Knox, Chloé Quélin, Cyril Mignot, Martin Chevarin, P. Callier, Diana Rodriguez, Alexis Arzimanoglou, Robert Olaso, David Geneviève, Arthur Sorlin, Sylvie Odent, Christel Thauvin, Victoria E. R. Parker, Pierre Vabres, Louise Goujon, Malika Keddar, Melissa Riachi, Sylvie Fraitag, Laurence Faivre, Emmanuelle Blanchard, Satyamaanasa Polubothu, Marie-Line Jacquemont, Jean-Baptiste Rivière, Anne Boland, Jean-François Deleuze, Paul Rollier, Véronique Darmency, Marie-Hélène Aubriot-Lorton, Yline Capri, V. Carmignac, Daniel Amram, Catherine Vincent-Delorme, Paul Kuentz, Marc Delepine, Didier Bessis, Robert K. Semple, Sarah Grotto, Veronica A. Kinsler, Laurent Guibaud, Christophe Philippe, Jean-Benoît Courcet, Apollo - University of Cambridge Repository, 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, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Cambridge [UK] (CAM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Great Ormond Street Hospital for Children [London] (GOSH), University College of London [London] (UCL), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pontchaillou [Rennes], AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHI Créteil, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL), 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), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), University of Edinburgh, and BOHAUD, FRANCOISE

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Melanocyte, Mechanistic Target of Rapamycin Complex 1, Article, 03 medical and health sciences, Tuberous sclerosis, Epilepsy, 0302 clinical medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Megalencephaly, Genetics (clinical), PI3K/AKT/mTOR pathway, Hypopigmentation, business.industry, Mosaicism, TOR Serine-Threonine Kinases, Macrocephaly, Correction, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, Immunostaining
Abstract

Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.

Published
2021
Full Text
View/download PDF

14. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author

Sylviane Marouillat, Marie-Laure Vuillaume, Thomas Smol, Rose-Anne Thépault, Lyse Ruaud, Sarah Grotto, Jamal Ghoumid, Nicolas Chatron, Annick Toutain, Marianne Till, Alain Verloes, Manon Dixneuf, Valérie Chune, Gaetan Lesca, Frédéric Laumonnier, Nathalie Couque, Bénédicte Gérard, Martine Raynaud, Judith Halewa, Dévina C. Ung, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ANR-20-CE17-0006,ASDecode,Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux(2020), Laumonnier, Frédéric, Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux - - ASDecode2020 - ANR-20-CE17-0006 - AAPG2020 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV]Life Sciences [q-bio], Mutation, Missense, autism spectrum disorder, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, functional analyses, PTCHD1 (patched domain containing 1) gene, 03 medical and health sciences, Mice, in vitro cellular models, subcellular localization, Genetics, medicine, Missense mutation, Animals, Humans, Gene, Genetics (clinical), Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Endoplasmic reticulum, 030305 genetics & heredity, Cell Membrane, Membrane Proteins, Subcellular localization, medicine.disease, In vitro, Transmembrane protein, Amino acid, [SDV] Life Sciences [q-bio], chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, missense variants, Research Article
Abstract

The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD., Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.

Published
2021
Full Text
View/download PDF

15. Correction to: Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Author

Catherine Sarret, Satyamaanasa Polubothu, V. Carmignac, Daniel Amram, Anne Boland, Chloé Quélin, Véronique Darmency, Christophe Philippe, Emmanuelle Blanchard, Martin Chevarin, P. Callier, Veronica A. Kinsler, Yannis Duffourd, Robert Olaso, Jean-Baptiste Rivière, Marie-Hélène Aubriot-Lorton, Sylvie Fraitag, Christel Thauvin, Malika Keddar, B. Catteau, Alexis Arzimanoglou, Cyril Mignot, Rachel G. Knox, Didier Bessis, Sarah Grotto, Robert K. Semple, Marie-Line Jacquemont, Arthur Sorlin, Sylvie Odent, David Geneviève, Laurent Guibaud, Melissa Riachi, Yline Capri, Pierre Vabres, Victoria E. R. Parker, Louise Goujon, Jean-Benoît Courcet, Laurence Faivre, Jean-François Deleuze, Paul Rollier, Marc Delepine, Catherine Vincent-Delorme, Paul Kuentz, Diana Rodriguez, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), and Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA)

Subjects
business.industry, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Computational biology, business, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), PI3K/AKT/mTOR pathway, Human genetics
Abstract

International audience

Published
2021
Full Text
View/download PDF

16. Dilated Cardiomyopathy and Premature Ovarian Failure Unveiling Propionic Aciduria

Author

Soumeya Bekri, Catherine Nafeh-Bizet, Stéphanie Gobin, Abdellah Tebani, Sarah Grotto, Bénédicte Sudrié-Arnaud, Bernadette Chadefaux-Vekemans, and Valérie Drouin-Garraud

Subjects
Adult, Cardiomyopathy, Dilated, 0301 basic medicine, medicine.medical_specialty, Propionic Acidemia, Clinical Biochemistry, Cardiomyopathy, Primary Ovarian Insufficiency, 030105 genetics & heredity, Gastroenterology, 03 medical and health sciences, Internal medicine, Idiopathic dilated cardiomyopathy, medicine, Humans, Ejection fraction, medicine.diagnostic_test, business.industry, Biochemistry (medical), Complete blood count, Dilated cardiomyopathy, medicine.disease, Antral follicle, Premature ovarian failure, Female, Macrocytic anemia, business
Abstract

A 28-year-old woman presented with premature ovarian failure (POF).8 She was the eldest of 4 children and her siblings were all healthy. She underwent heart transplantation at 17 years of age following acute cardiac decompensation due to hypokinetic dilated cardiomyopathy (DCM). At this time, her left ventricle ejection fraction collapsed to 20%, although no arrhythmia or conduction abnormalities were observed, and psychomotor and cognitive functions were normal. She was determined to have idiopathic dilated cardiomyopathy for which a genetic/metabolic etiology was not considered at the time. Posttransplantation follow-up was satisfactory, with normal cardiac function. During her most recent presentation with POF, she underwent endocrine function assessment for infertility. Concentrations of serum markers were highly suggestive of diminished ovarian reserve: follicle-stimulating hormone = 20 UI/L [reference interval (RI): 1.7–7.7]; estradiol = 59 pg/mL (RI: 50–230); anti-Mullerian hormone = 1 μg/L (RI: 2.5–6). The antral follicle count was 5, consistent with POF. Additional investigations, including thyroid hormone testing, karyotype, and fragile X study, were normal. Routine biochemistry testing, including plasma ammonia, bicarbonate, and electrolytes, was also unremarkable. A complete blood count revealed mild macrocytic anemia (hemoglobin = 11.1 g/dL, …

Published
2018
Full Text
View/download PDF

17. Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

Author

Alica M. Goldman, Frédéric Tran Mau-Them, Bertrand Isidor, Francesca Mattioli, Gaëlle Hayot, Piton Amélie, Jérémie Courraud, Jamel Chelly, Sarah Grotto, Ganka Douglas, Aida Telegrafi, Alicia Boughton, Sébastien Moutton, Mandel Jean-Louis, Christelle Golzio, Zohra Shad, Nathalie Drouot, Chantal Sellier, Yue Cindy Si, Elisabeth Kaplan, Sophie Nambot, Nolwenn Jean, Paul C. Van Ness, Candace Gamble, Angélique Quartier, Nicolas Charlet, Richard Dineen, and Maria-Victoria Hinckelmann

Subjects
Genetics, 0303 health sciences, Ataxia, NOVA2 Gene, Alternative splicing, Biology, Hypotonia, Frameshift mutation, 03 medical and health sciences, Splicing factor, 0302 clinical medicine, RNA splicing, medicine, medicine.symptom, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

Published
2019
Full Text
View/download PDF

18. TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A

Author

Simon Boussion, Sandra Whalen, Tania Attié-Bitach, Pierre-Simon Jouk, Dominique Carles, Sarah Grotto, Fabienne Escande, Florence Petit, Anne Bazin, Fanny Pelluard, Sylvie Manouvrier-Hanu, Louise Devisme, Perrine Brunelle, Yves Alembik, Céline Duhamel, Jamal Ghoumid, Thomas Smol, Charlotte Mechler, Alice Goldenberg, Laurence Loeuillet, Maryse Bonnière, Geneviève Baujat, Caroline Michot, Cyril Goizet, Philippe Carassou, Anne-Sophie Jourdain, Agnès Guichet, and Audrey Putoux

Subjects
Untranslated region, Adult, Male, Adolescent, Genetic counseling, Biology, Cohort Studies, 03 medical and health sciences, Young Adult, Genetics, medicine, Congenital Bone Marrow Failure Syndromes, Humans, Upper Extremity Deformities, Congenital, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Messenger RNA, TAR syndrome, 030305 genetics & heredity, Infant, Newborn, Infant, RNA-Binding Proteins, Middle Aged, medicine.disease, Null allele, Thrombocytopenia, Radius, Chromosomes, Human, Pair 1, Child, Preschool, RNA splicing, Exon junction complex, Female, Chromosome Deletion, 5' Untranslated Regions
Abstract

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5'-untranslated region (5'-UTR) and 3'-UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.

Published
2019

19. The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

Author

Stéphane Triau, Christel Thauvin-Robinet, Julien Thevenon, Guillaume Captier, David Geneviève, Audrey Putoux, Yannis Duffourd, Delphine Héron, Patrick Callier, Mirna Assoum, Laurence Faivre, Daphné Lehalle, Patrick Edery, Alice Goldenberg, Sarah Grotto, Bettina Bessières, Catherine Vincent-Delorme, Ange-Line Bruel, Hülya Kayserili, Christelle Cabrol, Nursel Elcioglu, Geneviève Baujat, Myriam Vezain, Alice Masurel, Massimiliano Rossi, Umut Altunoglu, Pierre Vabres, Pascale Saugier-Veber, Sandrine Marlin, 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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Departement of Genetics [University of Istanbul], Istanbul University, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Histologie Embryologie Cytogénétique [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), Département Chirurgie Pédiatrique [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), 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), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de foetopathologie (CHU d'Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Lille, Service de Dermatologie (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-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, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de chirurgie infantile [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de références des syndromes malformatifs et anomalies du développement [CHU Lyon], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de génétique clinique (CHU Lille), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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 du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Inheritance Patterns, 030105 genetics & heredity, frontonasal dysplasia, whole exome sequencing, Craniofacial Abnormalities, 0302 clinical medicine, Polymicrogyria, Eye Abnormalities, Ear, External, 10. No inequality, Child, Genetics (clinical), Exome sequencing, whole genome sequencing, Thyroid agenesis, Hypoplasia, DNA-Binding Proteins, Phenotype, Child, Preschool, Female, Respiratory System Abnormalities, medicine.medical_specialty, Adolescent, Quantitative Trait Loci, Oculoauriculofrontonasal syndrome, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Frontonasal dysplasia, Genetic Association Studies, Whole genome sequencing, Homeodomain Proteins, business.industry, Facial cleft, Skull, Infant, Newborn, Facies, Infant, 030206 dentistry, medicine.disease, Dermatology, Spine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dysplasia, business, Tomography, Spiral Computed, Transcription Factors
Abstract

IF 2.264; International audience; The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.

Published
2018
Full Text
View/download PDF

20. Chronic respiratory failure in myotonic dystrophy type 1 (DM1): Incidence & risk factors

Author

Antoine Cuvelier, Anne-Marie Guerrot, Marie-Anne Melone, Marie Netchitailo, Lucie Guyant-Maréchal, Alice Goldenberg, Maxime Patout, Sarah Grotto, Catherine Tardif, F. Portier, and Anne-Laure Bedat-Millet

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, business.industry, Incidence (epidemiology), University hospital, Single Center, medicine.disease, Myotonic dystrophy, Disease severity, Internal medicine, medicine, Cardiology, Respiratory system, Muscular dystrophy, business, Chronic respiratory failure
Abstract

Background: DM1 is the most frequent adult-onset muscular dystrophy. CTG length expansion has been correlated with disease severity. Incidence of chronic respiratory failure (CRF) is unknown. The aim of this study was to assess the incidence of CRF and its risk factors. Methods: Retrospective single center observational study including all patients with proven DM1 followed in Rouen University Hospital between 2000 and 2016. CRF was defined by home NIV requirement. Results: Eighty-six patients with DM1 were identified. Of these, 26 (30%) had CRF. Comparison of patients with or without CRF can be found in table 1. Adherence to home NIV was 5.6±3.6hours/day. CTG length was correlated to daytime PaCO 2 (r=0.366; p=0.01), sniff nasal inspiratory pressure (SNIP) (r=-0.391; p=0.008), maximal inspiratory pressure (MIP) (r=-0.530; p=0.001), maximal expiratory pressure (MEP) (r=-0.512; p=0.001) and cough peak flow (CPF) (r=-0.433; p=0.015). Conclusion: CRF is frequent in patients with DM1 and should be screened in all patients. CTG length expansion is correlated with respiratory muscles impairment but cannot predict home NIV requirement.

Published
2017
Full Text
View/download PDF

21. Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature

Author

Fabienne Giuliano, Olivier Pichon, Lucile Pinson, Bénédicte Duban-Bedu, Valérie Malan, Emilie Bourel-Ponchel, Rima Nabbout, Mathilde Nizon, Delphine Héron, Marlène Rio, Béatrice Bourgois, Odile Boute, Alice Goldenberg, Sarah Grotto, Sylvie Nusbaum, Odile Raoul, Catherine Turleau, Eric Le Galloudec, Joris Andrieux, Houda Karmous-Benailly, Bruno Delobel, Marie-Christine de Blois, Boris Keren, Martine Le Merrer, Laurence Colleaux, Cédric Le Caignec, Albert David, Serge Romana, Jean-Michel Lapierre, Agnès Roubertie, Didier Lacombe, Caroline Rooryck, Michel Vekemans, Michèle Mathieu-Dramard, and Anne-Gaëlle Le Moing

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Candidate gene, Adolescent, Chromosomal rearrangement, Epilepsy, Segmental Duplications, Genomic, Intellectual disability, Genetics, medicine, Humans, Child, Genetic Association Studies, Genetics (clinical), Segmental duplication, Chromosomes, Human, X, Comparative Genomic Hybridization, business.industry, Chromosome Mapping, Electroencephalography, West Syndrome, medicine.disease, Phenotype, Child, Preschool, Cohort, Female, business, Comparative genomic hybridization
Abstract

Array comparative genomic hybridization (array CGH) has proven its utility in uncovering cryptic rearrangements in patients with X-linked intellectual disability. In 2009, Giorda et al. identified inherited and de novo recurrent Xp11.23p11.22 microduplications in two males and six females from a wide cohort of patients presenting with syndromic intellectual disability. To date, 14 females and 5 males with an overlapping microduplication have been reported in the literature. To further characterize this emerging syndrome, we collected clinical and microarray data from 17 new patients, 10 females, and 7 males. The Xp11.23p11.2 microduplications detected by array CGH ranged in size from 331 Kb to 8.9 Mb. Five patients harbored 4.5 Mb recurrent duplications mediated by non-allelic homologous recombination between segmental duplications and 12 harbored atypical duplications. The chromosomal rearrangement occurred de novo in eight patients and was inherited in six affected males from three families. Patients shared several common major characteristics including moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep. Atypical microduplications allowed us to identify minimal critical regions that might be responsible for specific clinical findings of the syndrome and to suggest possible candidate genes: FTSJ1 and SHROOM4 for intellectual disability along with PQBP1 and SLC35A2 for epilepsy. Xp11.23p11.22 microduplication is a recently-recognized syndrome associated with intellectual disability, epilepsy, and early onset of puberty in females. In this study, we propose several genes that could contribute to the phenotype.

Published
2014
Full Text
View/download PDF

22. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Author

Anne-Marie Guerrot, Joelle Roume, Thierry Frebourg, Patricia Faure, Pascale Saugier-Veber, Sylvain Renolleau, Séverine Audebert-Bellanger, Gilles Morin, Isabelle Desguerre, Renaud Touraine, Ghislaine Plessis, Séverine Drunat, Marjolaine Willems, Sarah Grotto, Hubert Journel, Eric Verspyck, Brigitte Simon-Bouy, Jean-Marie Cuisset, Anne-Gaëlle Grebille, Stéphane Marret, Vincent Flurin, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de neurologie pédiatrique [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), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), 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), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Centre Hospitalier de Versailles André Mignot (CHV), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Service de gynécologie et obstétrique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Heart Defects, Congenital, Male, 0301 basic medicine, Weakness, Pediatrics, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], SMN1, Spinal Muscular Atrophies of Childhood, Ultrasonography, Prenatal, 03 medical and health sciences, Life Expectancy, 0302 clinical medicine, medicine, Humans, Increased nuchal translucency, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Respiratory Distress Syndrome, Newborn, Pregnancy, Reflex, Abnormal, business.industry, Homozygote, Infant, Newborn, Muscle weakness, Spinal muscular atrophy, medicine.disease, SMA, Survival of Motor Neuron 1 Protein, Cranial Nerve Diseases, Hypotonia, 3. Good health, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Autonomic Nervous System Diseases, Neurology, Muscle Hypotonia, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Results Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

Published
2016
Full Text
View/download PDF

23. Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly

Author

Janneke H M Schuurs-Hoeijmakers, Thierry Frebourg, Hans van Bokhoven, Sarah Grotto, Pascal Chambon, Séverine Fehrenbach, Helen Puusepp-Benazzouz, Valérie Drouin-Garraud, Pascale Saugier-Veber, Nathalie Le Meur, Arjan P.M. de Brouwer, and Katrin Õunap

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Nonsense mutation, DNA Mutational Analysis, Cubitus valgus, Kyphosis, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Scoliosis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, X, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, business.industry, Macrocephaly, General Medicine, medicine.disease, Megalencephaly, Pedigree, Codon, Nonsense, 030220 oncology & carcinogenesis, Speech delay, medicine.symptom, business, Transcription Factors
Abstract

Item does not contain fulltext Truncating mutations of the BRWD3 gene have been reported in two distinct families with in total four patients so far. By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability. In addition, by using exome sequencing, we ascertained a family with a BRWD3 nonsense mutation, p.Tyr1131*, in four males with intellectual disability. We compared the clinical presentation of these five patients to that of the four patients already described in the literature for further delineation of the clinical spectrum in BRWD3-related intellectual disability. The main symptoms are mild to moderate intellectual disability (n = 9/9) with speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6), and skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results