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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
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2. Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic

Author

Laure Delaval, Karine Nguyen, J. Cogez, Romain Schneckenburger, Eric Jouvent, Valérie Lauer, Fatoumata Ba, Matthias Lamy, Cédric Urbanczyk, Igor Raynouard, Françoise Bergametti, Jérémie Dassa, Livia Lanotte, Valérie Layet, Elisabeth Tournier-Lasserve, Jean Philippe Neau, Mira Didic, Alexandru Florea, Cédric Gollion, Carmen Badiu, Thibault Coste, Dominique Hervé, Nathalie Derache, and Maude Grelet

Subjects
Male, Proband, Genetics, Heterozygote, Mutation, Brain, High-Temperature Requirement A Serine Peptidase 1, Middle Aged, Biology, medicine.disease_cause, Penetrance, eye diseases, Stop codon, Pedigree, Frameshift mutation, Codon, Nonsense, medicine, Humans, Missense mutation, Female, Neurology (clinical), Allele, Frameshift Mutation, Haploinsufficiency, Aged
Abstract

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10−17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10−18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10−5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.

Published
2021
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3. Congenital Central Hypothyroidism Caused by a Novel IGSF1 Variant Identified in a French Family

Author

Rachel Fourneaux, Sarah Castets, Alice Godefroy, Maude Grelet, Juliette Abeillon-du Payrat, Alexandru Saveanu, Frederic Castinetti, Rachel Reynaud, 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 d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), Institut Marseille Maladies Rares (MarMaRa), Centre de référence des maladies rares de l'hypophyse (HYPO), Service d'Endocrinologie, Diabète et Maladies Métaboliques, Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Saint-Joseph [Marseille], Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
Immunoglobulin superfamily member 1, endocrine system, [SDV.GEN]Life Sciences [q-bio]/Genetics, Endocrinology, Endocrinology, Diabetes and Metabolism, Pediatrics, Perinatology and Child Health, Congenital central hypothyroidism, Neurodevelopment, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Neonatal central hypothyroidism
Abstract

Introduction: Congenital central hypothyroidism (CCH) is a rare disorder that can be caused by X-linked mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. Here, we describe four familial cases with a variable presentation due to a novel IGSF1 pathogenic variant. Case Presentation: In the index case, an investigation at birth of a suspected brain-lung-thyroid syndrome surprisingly revealed a central hypothyroidism. Next-generation sequencing uncovered a novel IGSF1 pathogenic variant: a hemizygous single base duplication (G) resulting in a premature stop codon (NM_001555.4: c.2485dup, p.Ala829Glyfs*15). Further family investigations revealed missed neonatal CCH for the older brother who presented with prolonged jaundice (thyroid stimulating hormone 3.06 mUI/L, FT4 9.4 pmol/L, FT3 4.2 pmol/L). It also led to the diagnosis of CCH at 11 months of age for the younger brother, whose thyroid function was considered normal at birth. Neuropsychological evaluations showed no cognitive impairment for the eldest two brothers, but a slightly reduced processing-speed index compared with the other parameters for the oldest. Furthermore, a maternal uncle was diagnosed with biochemical CCH at 34 years of age, despite having few symptoms, and a complete workup revealed prolactin deficiency and macroorchidism. Discussion: This report of a rare case of neonatal CCH caused by IGSF1 deficiency highlights the importance of recognizing the neonatal signs of hypothyroidism to diagnose CCH as early as possible. Our results also show the importance of performing family genetic screening if a pathogenic variant is identified, to properly monitor carriers as CCH may develop over time. We suggest that these families should be followed up in the long term to better understand the natural history of this syndrome and evaluate the need for hormone substitution.

Published
2022
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4. Fetal megacystis‐microcolon: Genetic mutational spectrum and identification of <scp> PDCL3 </scp> as a novel candidate gene

Author

Cécile Masson, Arnaud Molin, Clarisse Billon, Agnès Liard, Lucile Boutaud, Sabine Sigaudy, Sophie Thomas, Eglantine Magnin, Radia Fritih, Valérie Layet, Maryse Bonnière, Yves Ville, Alix Clemenson, Alain Diguet, Philippe Roth, Coralie Dauge, Sophie Patrier, John Rendu, Julia Tantau, Bettina Bessières, Alice Goldenberg, Leila Hakkakian, Céline Poirsier, Tania Attié-Bitach, Ferechté Razavi, Clémence Fleury, Eric Verspyck, Nadia Elkhartoufi, Maude Grelet, Amale Achaiaa, Fabienne Prieur, Christine Bole-Feysot, and Aude Tessier

Subjects
Male, 0301 basic medicine, Candidate gene, Myosin Light Chains, Colon, Urinary Bladder, Nerve Tissue Proteins, 030105 genetics & heredity, Biology, Compound heterozygosity, 03 medical and health sciences, Exome Sequencing, Fetal megacystis, Genetics, MYH11, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Gene, Genetics (clinical), Exome sequencing, Myosin Heavy Chains, Homozygote, Intestinal Pseudo-Obstruction, Infant, Newborn, MYLK, Microcolon, Actins, Pedigree, 030104 developmental biology, Aborted Fetus, Mutation, Female, Carrier Proteins
Abstract

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.

Published
2020
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5. Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49

Author

Mario Abaji, Svetlana Gorokhova, Nathalie Da Silva, Tiffany Busa, Maude Grelet, Chantal Missirian, Sabine Sigaudy, Nicole Philip, France Leturcq, Nicolas Lévy, Martin Krahn, Marc Bartoli, 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), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de génétique médicale [Hôpital de la Timone - APHM], and 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)

Subjects
muscular dystrophy, therapy, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle Fibers, Skeletal, Exons, Oligonucleotides, Antisense, Dystrophin, Muscular Dystrophy, Duchenne, AON, genetics, pathological mechanisms, DMD, deletion, exon skipping, myopathy, Humans, Genetics (clinical)
Abstract

International audience; Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49.

Published
2022
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6. SATB2-associated syndrome: first report of a gonadal and somatic mosaicism for an intragenic copy number variation

Author

Nicole Philip, Chantal Missirian, Jérémie Mortreux, Emilie Alazard, Maude Grelet, and Sabine Sigaudy

Subjects
Male, DNA Copy Number Variations, Germline mosaicism, Real-Time Polymerase Chain Reaction, Pathology and Forensic Medicine, Humans, Medicine, Genetic Predisposition to Disease, Copy-number variation, Genetic Association Studies, In Situ Hybridization, Fluorescence, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Mosaicism, business.industry, Facies, Matrix Attachment Region Binding Proteins, Syndrome, General Medicine, Pedigree, Phenotype, Somatic mosaicism, Pediatrics, Perinatology and Child Health, Female, Anatomy, business, Transcription Factors
Abstract

Gonadal mosaicism has been reported in a variety of dominant or X-linked conditions and should be considered in all cases of apparent de-novo variation. Recently, some cases of supposed parental germline mosaicism have been shown to result from low-level somatic mosaicism. In most of the cases, mosaicism has been reported for pathogenic single nucleotide variants with only a few cases of copy number variation mosaicism described so far. Herein, we present the first case of parental somatic and gonadal copy number variation mosaicism in the SATB2 gene. We report three brothers presenting with the SATB2-associated syndrome. They all carry the same 121-kb heterozygous intragenic deletion of SATB2. Parental somatic mosaicism was detected by array-comparative genomic hybridization on a maternal blood sample and confirmed by Fluorescence in situ hybridization analysis on blood and buccal cells. This clinical report highlights the importance of investigating for parental somatic mosaicism to estimate the proper recurrence risk for subsequent pregnancy.

Published
2019
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7. Analysis of HOXB1 gene in a cohort of patients with sporadic ventricular septal defect

Author

Gwenaëlle Collod-Béroud, Joséphine Okoronkwo, Damien Bonnet, Julia Mitchell, Nathalie Eudes, Amélie Pinard, Stéphane Zaffran, Fanny Bajolle, Maude Grelet, 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), and ANR-13-BSV2-0003,TransCARDIAC,Réseau transcriptionnel controllant la différenciation des progéniteurs cardiaques du second champ cardiaque.(2013)

Subjects
Heart Defects, Congenital, Heart Septal Defects, Ventricular, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, animal structures, Ventricular septal defect, Cohort Studies, 03 medical and health sciences, Double outlet right ventricle, Internal medicine, Genetics, Humans, Medicine, Variant, Child, Molecular Biology, Gene, Congenital heart disease, Homeodomain Proteins, business.industry, General Medicine, medicine.disease, Double Outlet Right Ventricle, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, embryonic structures, Cohort, Etiology, Cardiology, Female, business, HOXB1, Transcription Factors
Abstract

International audience; Ventricular septal defect (VSD) including outlet VSD of double outlet right ventricle (DORV) and perimembranous VSD are among the most common congenital heart diseases found at birth. HOXB1 encodes a homeodomain transcription factor essential for normal cardiac outflow tract development. The aim of the present study was to investigate the possible genetic effect of sequence variations in HOXB1 on VSD. The coding regions and splice junctions of the HOXB1 gene were sequenced in 57 unrelated VSD patients. As a result, a homozygous c.74\₈2dup (p.Pro28delinsHisSerAlaPro) variant was identified in one individual with DORV. We also identified five previously reported polymorphisms (rs35114525, rs12946855, rs14534040, rs12939811, and rs7207109) in 18 patients (12 DORV and 6 perimembranous VSD). Our study did not show any pathogenic alterations in the coding region of HOXB1 among patients with VSD. To our knowledge this is the first study investigating the role of HOXB1 in nonsyndromic VSD, which provide more insight on the etiology of this disease.

Published
2018
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8. Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Author

Thierry Bienvenu, Sarah Baer, Yves Alembik, Laurent Pasquier, A.S. Lebre, Elise Schaefer, Sylvie Sukno, Caroline Nava, Cindy Colson, Didier Lacombe, Michèle Mathieu-Dramard, Valérie Cormier-Daire, Thomas Smol, Delphine Héron, Alice Goldenberg, Odile Boute, Martine Doco-Fenzy, Julien Thevenon, David Geneviève, Boris Keren, Nicole Philip, Catherine Vincent-Delorme, Sophie Rondeau, Alexandra Afenjar, Bruno Delobel, Damien Haye, G. Boursier, Marjolaine Willems, Amélie Piton, Mélanie Fradin, Alice Masurel, A. Petit, Bénédicte Gérard, Bertrand Isidor, Marie-Pierre Cordier, Pascale Saugier-Veber, Gilles Morin, Gaetan Lesca, Julien Van-Gils, Bénédicte Duban-Bedu, Maude Grelet, Juliette Piard, Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], 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), 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), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Production du lait (PL), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), 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), Service de génétique clinique, Hôpital Sud, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), FHU TRANSLAD, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-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)-Université de Paris (UP), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Pontchaillou [Rennes], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Marseille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Bordeaux [Bordeaux], Institut des Sciences de la mécanique et Applications industrielles (IMSIA - UMR 9219), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, 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), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint Vincent de Paul de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], International Livestock Research Institute, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Biologie Fonctionnelle, Insectes et Interactions (BF2I), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Hematology, Le CHCB, Centre Hospitalier de la Côte Basque, CHU Pitié-Salpêtrière [APHP], EDF (EDF), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Neonatal Pediatrics, Rouen University Hospital, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université catholique de Lille (UCL), 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), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-EDF R&D (EDF R&D), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Hypertrichosis, Male, Pediatrics, [SDV]Life Sciences [q-bio], MESH: Magnetic Resonance Imaging, Pathognomonic, MESH: Child, Intellectual disability, MESH: Syndrome, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, biology, Wiedemann-Steiner syndrome, High-Throughput Nucleotide Sequencing, Syndrome, KMT2A, MESH: Amino Acid Substitution, Magnetic Resonance Imaging, hypertrichosis, 3. Good health, hairiness, Phenotype, Child, Preschool, cardiovascular system, Female, Disease Susceptibility, France, medicine.symptom, MESH: Tomography, X-Ray Computed, Myeloid-Lymphoid Leukemia Protein, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Disease Susceptibility, MESH: Phenotype, Short stature, MESH: Intellectual Disability, 03 medical and health sciences, Hypertrichosis cubiti, Intellectual Disability, Genetics, medicine, Humans, histone methylation, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, medicine.disease, MESH: Male, MESH: France, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, MESH: Myeloid-Lymphoid Leukemia Protein, Mutation, biology.protein, business, Tomography, X-Ray Computed, MESH: Female
Abstract

International audience; Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Published
2017
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