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13 results on '"François Lecoquierre"'

1. Variants in GNAI1 Cause a Syndrome Associated with Variable Features including Developmental Delay, Seizures and Hypotonia

Author

Lauren Brady, Bryan E. Hainline, Konrad Platzer, Muhammad Zafar, Corinna Powell, Darcy J. Huismann, Heather C Mefford, Afnan Alhakeem, Daniel G. MacArthur, Alison M. Muir, Trevor L Hoffman, Mark A. Tarnopolsky, François Lecoquierre, Lindsay Rhodes, Tilman Polster, Susanne Axer-Schaefer, Alice Goldenberg, Katherine Sapp, Caoimhe S. McKenna, Jasper J. van der Smagt, Tara Montgomery, Eleina M. England, Brianna K. Murray, Myriam Srour, Lia Zitano, William B. Dobyns, Grace Noh, Angela F. Brady, Lindsey Sawyer, Ingrid M. Wentzensen, Holly Dubbs, Jane Juusola, Richard Caswell, Richard H. van Jaarsveld, Danielle DeMarzo, Samantha A. Schrier Vergano, Caleb Bupp, Grace E. VanNoy, Jose E. Martinez, Melanie O’Leary, Iris M de Lange, Shane McKee, Golder N. Wilson, Rhonda E. Schnur, Meira Meltzer, Vinod Varghese, Kristin G. Monaghan, Carole Brewer, Carolyn Tysoe, Jennifer F. Gardner, Ethan M. Goldberg, Shelagh Joss, Andrea Accogli, Chiara Klöckner, Andrea L. Gropman, and Pradeep C. Vasudevan

Subjects
0301 basic medicine, Developmental Disabilities, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Epilepsy, Neurodevelopmental disorder, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, medicine, Humans, Global developmental delay, Child, Genetics (clinical), Exome sequencing, Genetics, Genetic heterogeneity, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Muscle Hypotonia, medicine.symptom
Abstract

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Published
2021

2. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Male, Bioinformatics, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, MESH: Child, Intellectual disability, Missense mutation, MESH: Obesity, MESH: Genetic Variation, MESH: Nerve Tissue Proteins, Child, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, 0303 health sciences, MESH: Transcription Factors, MESH: Infant, 3. Good health, Phenotype, MESH: Feeding and Eating Disorders, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, Learning disability, Female, medicine.symptom, Adult, Heterozygote, Adolescent, Language delay, Nerve Tissue Proteins, Biology, MESH: Phenotype, MESH: Language Development Disorders, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Language Development Disorders, Obesity, Genetic Association Studies, 030304 developmental biology, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Genetic Variation, Infant, MESH: Adult, medicine.disease, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Autism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

Published
2022

3. Haploinsufficiency of the Primary Familial Brain Calcification Gene <scp> SLC20A2 </scp> Mediated by Disruption of a Regulatory Element

Author

Christel Thauvin-Robinet, Benoit Delpont, Anne Boland, Robert Olaso, Thierry Frebourg, François Lecoquierre, Pascal Chambon, Anne-Claire Richard, Jean-Luc Battini, Gaël Nicolas, Anne Rovelet-Lecrux, Kévin Cassinari, Dominique Campion, Camille Charbonnier, Olivier Quenez, Jean-François Deleuze, Sandrine Tury, Dorothée Pouliquen, and Jean-François Besancenot

Subjects
0301 basic medicine, Brain Diseases, DNA Copy Number Variations, Sodium-Phosphate Cotransporter Proteins, Type III, HEK 293 cells, Brain, Haploinsufficiency, Biology, Molecular biology, Reverse transcriptase, 03 medical and health sciences, HEK293 Cells, 030104 developmental biology, 0302 clinical medicine, Neurology, Mutation, Humans, Neurology (clinical), Copy-number variation, Allele, Enhancer, Gene, 030217 neurology & neurosurgery, Exome sequencing
Abstract

OBJECTIVE Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes. METHODS After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9). RESULTS The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P

Published
2020

4. Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Author

Marianne Begorre, Daniel Cailliez, Claire Beneteau, Pierre Chenal, Thierry Frebourg, Guillaume Benoist, François Lecoquierre, Raphaele Mangione, Florence Petit, Nicolas Gruchy, Louise Devisme, Sophie Patrier, Juliette Coursimault, Fanny Pelluard, Hubert Journel, Bénédicte Gérard, Marion Gérard, Pascale Saugier-Veber, Valérie Layet, Alain Liquier, Corinne Jeanne, Mirjam M. de Jong, Nadia Tillouche, Anne Bazin, Gaël Nicolas, Conny M. A. van Ravenswaaij-Arts, Anne-Claire Brehin, Wilfrid Finck, Sophie Coutant, Sophie Degre, Christine Francannet, Madeleine Joubert, Hélène Laurichesse Delmas, 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), Laboratoire CERBA [Saint Ouen l'Aumône], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lausanne = University of Lausanne (UNIL), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe Hospitalier du Havre, University of Groningen [Groningen], Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique prénatale [CHU Caen], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Genotype, audal dysgenesis, Ectromelia, [SDV]Life Sciences [q-bio], REQUIREMENT, Malformation sequence, Biology, Sirenomelia, CAUDAL REGRESSION, Frameshift mutation, 03 medical and health sciences, Genetics, medicine, Humans, CDX2 Transcription Factor, Genetic Predisposition to Disease, CDX2, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Calcium-Binding Proteins, 030305 genetics & heredity, Wnt signaling pathway, Heterozygote advantage, DEFECTS, medicine.disease, caudal dysgenesis, de novo mutation, Pedigree, Phenotype, Amino Acid Substitution, GROWTH, Female, CDX2 de novo mutation, exome sequencing
Abstract

Full access; International audience; Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio‐based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2 . We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Published
2020

5. Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders

Author

Sebastien Moutton, Martin Chevarin, Nada Houcinat, Sophie Nambot, Yannis Duffourd, Laurence Faivre, Anne-Laure Mosca-Boidron, François Lecoquierre, Christel Thauvin-Robinet, Julian Delanne, Alice Masurel-Paulet, Arthur Sorlin, Charlotte Poe, Caroline Racine, Marjolaine Willems, Julien Thevenon, Steven A. Kushner, David Geneviève, Ange-Line Bruel, Patrick Callier, Frédéric Tran Mau-Them, Christophe Philippe, Emilie Tisserant, Thibaut Jouan, Christine Coubes, Antonio Vitobello, Nolwenn Jean-Marçais, Daphné Lehalle, Femke M.S. de Vrij, and Psychiatry

Subjects
Male, Candidate gene, Developmental Disabilities, Population, Biology, Compound heterozygosity, 03 medical and health sciences, Intellectual Disability, Genotype, Exome Sequencing, Genetics, Humans, Exome, Genetic Predisposition to Disease, education, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Genomics, Phenotype, Human genetics, Female
Abstract

Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.

Published
2020

6. Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants

Author

Sebastien Moutton, Antonio Vitobello, Laurence Faivre, Christophe Philippe, Christel Thauvin-Robinet, Philippine Garret, Thibaud Jouan, Martin Chevarin, Benoit Urteaga, Yannis Duffourd, Sophie Nambot, Frédéric Tran-Mau-Them, Arthur Sorlin, François Lecoquierre, Ange-Line Bruel, and Christine Coubes

Subjects
Male, 0301 basic medicine, Candidate gene, Developmental Disabilities, Mutation, Missense, 030105 genetics & heredity, Biology, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Databases, Genetic, Intellectual disability, medicine, Humans, Missense mutation, Exome, Genetic Predisposition to Disease, Genetic Testing, Autistic Disorder, Gene, Genetics (clinical), Exome sequencing, Genetics, Computational Biology, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, medicine.disease, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Female, Transcription Factors
Abstract

Next-generation sequencing has revealed the major impact of de novo variants (DNVs) in developmental disorders (DD) such as intellectual disability, autism, and epilepsy. However, a substantial fraction of these predicted pathogenic DNVs remains challenging to distinguish from background DNVs, notably the missense variants acting via nonhaploinsufficient mechanisms on specific amino acid residues. We hypothesized that the detection of the same missense variation in at least two unrelated individuals presenting with a similar phenotype could be a powerful approach to reveal novel pathogenic variants. We looked for variations independently present in both our database of >1200 solo exomes and in denovo-db, a large, publicly available collection of de novo variants identified in patients with DD. This approach identified 30 variants with strong evidence of pathogenicity, including variants already classified as pathogenic or probably pathogenic by our team, and also several new variants of interest in known OMIM genes or in novel genes. We identified FEM1B and GNAI2 as good candidate genes for syndromic intellectual disability and confirmed the implication of ACTL6B in a neurodevelopmental disorder. Annotation of local variants with denovo-db can highlight missense variants with high potential for pathogenicity, both facilitating the time-consuming reanalysis process and allowing novel DD gene discoveries.

Published
2019

7. Author response for 'Homozygous TRAPPC11 truncating variant revealing segmental uniparental disomy of chromosome 4 as a cause of a recessive limb-girdle muscular dystrophy-18'

Author

Nawale Hadouiri, Marie-Gabrielle Mourot De Rougemont, Olivier Blanchard, Yannis Duffourd, Christel Thauvin-Robinet, Stéphanie Perez-Martin, François Lecoquierre, Antonio Vitobello, Arthur Sorlin, Benoit Colomb, Christophe Philippe, Véronique Darmency, Paul Ornetti, Quentin Thomas, Ange-Line Bruel, Laurence Faivre, and Véronique Dulieu

Subjects
Genetics, Chromosome 4, medicine, Biology, medicine.disease, Uniparental disomy, Limb-girdle muscular dystrophy
Published
2021

8. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Julien Van-Gils, Kyoko Takano, Victor P. Pedro, Lauren Brick, Pascale Saugier-Veber, Tugce B. Balci, Antonio Vitobello, Marielle Alders, Justine Rousseau, Frédéric Laumonnier, Christel Thauvin-Robinet, Raoul C.M. Hennekam, Tjitske Kleefstra, Matt Tedder, Jennifer Kerkhof, Damien Sanlaville, Gaël Nicolas, François Lecoquierre, Delphine Héron, Hanxin Lin, Sophie Rondeau, Mariya Kozenko, Simone Pizzi, Alexandra Afenjar, Victoria Mok Siu, Christèle Dubourg, David Geneviève, Erfan Aref-Eshghi, Solveig Heide, Barbara R. DuPont, Peter Ainsworth, David I. Rodenhiser, Boris Keren, Nicole de Leeuw, Sandra Whalen, Martine Raynaud, Damien Ulveling, Nathalie Ruiz-Pallares, Valérie Cormier-Daire, Mouna Barat-Houari, Michael A. Levy, Roger E. Stevenson, Jennifer A. Lee, Steven A. Skinner, Alan Graham Stuart, Laurence Faivre, Marie Shaw, Gaetan Lesca, Peter Henneman, Thierry Bienvenu, Marco Tartaglia, Charles E. Schwartz, Andrea Ciolfi, Michael J. Friez, Michael Field, Mike Kadour, Guillaume Velasco, Jozef Gecz, Claire Francastel, Didier Lacombe, Philippe M. Campeau, Jean-Christophe Andrau, Bekim Sadikovic, Marcel M.A.M. Mannens, Jennifer Masters, Cyril Mignot, Patricia Fergelot, Nicolas Chatron, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, General Paediatrics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Quality of Care, London Health Sciences Center (LHSC), Schulich School of Medicine and Dentistry, University of Western Ontario (UWO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Medical Center [Amsterdam], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan], IRCCS San Raffaele Scientific Institute [Milan, Italie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Sainte Justine [Montréal], McMaster University [Hamilton, Ontario], University of Tasmania [Hobart, Australia] (UTAS), Shinshu University Hospital, Radboud University Medical Center [Nijmegen], Hunter Genetics, University of Notre Dame [Indiana] (UND), University of South Australia [Adelaide], The Greenwood Genetic Center, Greenwood Genetic Center [Greenwood, South Carolina, USA], 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), Amsterdam Reproduction and Development Institute, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre épigénétique et destin cellulaire (EDC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Computational biology, 030105 genetics & heredity, Biology, Pediatrics, Article, Cohort Studies, molecular diagnostics, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, Gene duplication, Genetics, Humans, Hunter-McAlpine syndrome, Genetics (clinical), Mass screening, 030304 developmental biology, EpiSign, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA methylation, Genetic heterogeneity, 030305 genetics & heredity, Correction, Syndrome, DNA Methylation, Molecular diagnostics, Phenotype, Penetrance, Human genetics, 3. Good health, episignature, genomic DNA, 030104 developmental biology, Neurodevelopmental Disorders, uncertain clinical cases, Mendelian inheritance, symbols, Identification (biology), VUS classification
Abstract

Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access) Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Published
2020

9. Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes

Author

Maud Blanluet, Jacqueline Bou, Jacques Mauillon, Sandrine Manase, Steeve Fourneaux, Stéphanie Baert-Desurmont, Olivier Quenez, Julie Tinat, Marion Gérard, François Lecoquierre, Emilie Bouvignies, Myriam Vezain, Régine Marlin, Mathias Schwartz, Raphaël Lanos, Thierry Frebourg, Isabelle Tournier, Pierre Macquere, Sophie Coutant, Stéphanie Vasseur, Gaëlle Bougeard, Françoise Charbonnier, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)

Subjects
Adult, Male, 0301 basic medicine, Sequence analysis, Alu element, Computational biology, 030105 genetics & heredity, Biology, Sensitivity and Specificity, Article, 03 medical and health sciences, Exon, MUTYH, Genetics, medicine, Humans, Genetic Testing, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Massive parallel sequencing, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Introns, digestive system diseases, Lynch syndrome, 3. Good health, MSH6, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MSH2, Female, Colorectal Neoplasms
Abstract

We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Thanks to this strategy, we detected overlapping phenotypes (e.g., MUTYH biallelic mutations mimicking Lynch syndrome), mosaic alterations and complex SVs such as a genomic deletion involving the last BMPR1A exons and PTEN, an Alu insertion within MSH2 exon 8 and a mosaic deletion of STK11 exons 3–10. This strategy allows, in a single step, detection of all types of CRC gene alterations including SVs and provides a high disease-causing variant detection rate, thus optimizing the diagnosis of inherited CRC.

Published
2018

10. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

Author

Florence Demurger, Christine Binquet, Muriel Holder, Frédéric Tran Mau-Them, Salima El Chehadeh, Martine Doco-Fenzy, Geneviève Baujat, Delphine Héron, Judith St-Onge, Christophe Philippe, Elodie Gautier, Robert Olaso, Rebecca A. Barnard, Paul Kuentz, François Lecoquierre, Stanislas Lyonnet, Gwenaëlle Collod-Béroud, Dominique Martin-Coignard, Isabelle Missotte, Anne Boland, Cyril Goizet, Laurence Perrin, Valérie Cormier-Daire, Sébastien Moutton, Nadine Hanna, Jean-François Deleuze, Audrey Putoux, Guillaume Jondeau, Sylvie Odent, Doris Lechner, Arnold Munnich, Thibaud Jouan, Aurélia Jacquette, Pierre-Simon Jouk, Martin Chevarin, Virginie Carmignac, Elisabetta Lapi, Alice Goldenberg, Christel Thauvin-Robinet, Sujatha Jagadeesh, P. Callier, Fatma Daoud, Yannis Duffourd, Frédéric Huet, Nathalie Marle, Charlotte Poe, Gipsy Lopez, Cyril Mignot, Florence Petit, Khadija Amarof, Brian J. O'Roak, Caroline Cabret, Fanny Morice-Picard, Jean Baptiste Rivière, Mirna Assoum, Marie Ange Delrue, Julien Thevenon, Laurence Faivre, David Geneviève, Elisabeth Sarrazin, Ange Line Bruel, Pauline Arnaud, Catherine Boileau, Christine Coubes, Didier Lacombe, Laurence Duplomb, Alice Masurel, Patrick Collignon, Antonio Vitobello, Julien Van-Gils, Bruno Leheup, Nolwenn Jean-Marçais, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Le Mans (CH Le Mans), CHU Pitié-Salpêtrière [AP-HP], Hôpital Robert Debré Paris, Hôpital Robert Debré, Hospices Civils de Lyon (HCL), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], Centre hospitalier territorial Gaston-Bourret [Nouméa], CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), 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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Université Paris-Saclay, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Proband, Male, [SDV]Life Sciences [q-bio], intellectual deficiency, MESH: NFI Transcription Factors, chromatin remodeling, Marfan Syndrome, Craniofacial Abnormalities, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Mental Retardation, X-Linked, Exome, Child, de novo variants, Genetics (clinical), Exome sequencing, Genetics, MESH: Exome, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, NFIX, MESH: Young Adult, Female, Adult, MESH: Mutation, Adolescent, Chromatin remodeling, MESH: Intellectual Disability, MESH: Marfan Syndrome, EHMT1, Young Adult, MESH: Whole Exome Sequencing, Intellectual Disability, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, marfanoid habitus, Gene, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, Genetic heterogeneity, MESH: Chromatin Assembly and Disassembly, MESH: Histone-Lysine N-Methyltransferase, MESH: Adult, Histone-Lysine N-Methyltransferase, medicine.disease, Chromatin Assembly and Disassembly, MESH: Male, NFI Transcription Factors, Neurodevelopmental Disorders, Mutation, biology.protein, Mental Retardation, X-Linked, MESH: Female
Abstract

PurposeMarfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.MethodsTo further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.ResultsWe identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.ConclusionWe demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Published
2019

11. Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

Author

Patrick Edery, Flavie Diguet, Thomas Simonet, Cédric Le Caignec, Gaël Nicolas, Stéphanie Baert-Desurmont, Claire Bardel, Pascale Saugier-Veber, Damien Sanlaville, Jordi Corominas Galbany, Gaetan Lesca, Pierre Lindenbaum, Olivier Quenez, Nicolas Chatron, Pierre-Antoine Rollat-Farnier, Anne-Claude Tabet, Eduardo Calpena, Yline Capri, Caroline Schluth-Bolard, Bertrand Isidor, Annick Toutain, Kévin Cassinari, François Lecoquierre, Andrew O.M. Wilkie, Audrey Labalme, Olivier Pichon, Marie-Pierre Buisine, Jonathan Levy, 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU de Lyon, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, École normale supérieure - Rennes (ENS Rennes), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Gatonero SA, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Génétique du cancer et des maladies neuropsychiatriques (GMFC), 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), École normale supérieure de Lyon (ENS de Lyon)-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), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Groupement Hospitalier Lyon-Est (GHE), and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)

Subjects
Adult, Male, Adolescent, Retroelements, Locus (genetics), Retrotransposon, Computational biology, Biology, DNA sequencing, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Child, Exome, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Genetic testing, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, Diagnostic Tests, Routine, 030305 genetics & heredity, Genetic Variation, High-Throughput Nucleotide Sequencing, Infant, Middle Aged, Long interspersed nuclear element, Child, Preschool, Female, Mobile genetic elements, Reference genome
Abstract

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

Published
2019

12. Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene

Author

Homa Adle-Biassette, François Lecoquierre, Yline Capri, Alice Goldenberg, Annie Laquerrière, M. Brasseur-Daudruy, Valérie Layet, Fabien Guimiot, Sophie Patrier, Marion Gérard, Pascale Saugier-Veber, Sara Cipriani, Florent Marguet, and Thierry Frebourg

Subjects
Adult, 0301 basic medicine, Pathology, medicine.medical_specialty, Neuropathology, Ventricular system, Biology, lcsh:RC346-429, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Loss of Function Mutation, Foetal hydrocephalus, Ependyma, medicine, Humans, Family, lcsh:Neurology. Diseases of the nervous system, Medulla, Tight junction, Research, Homozygote, Membrane Proteins, Anatomy, MPDZ pathogenic variants, medicine.disease, Phenotype, Autosomal recessive inheritance, Multifocal malformation of the ependyma, 3. Good health, Hydrocephalus, Fetal Diseases, 030104 developmental biology, medicine.anatomical_structure, Female, Neurology (clinical), Choroid, Carrier Proteins
Abstract

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

Published
2017

13. Clinical and Molecular Findings in 39 Patients with KBG Syndrome Caused by Deletion or Mutation of ANKRD11

Author

Aurélia Jacquette, Alice Goldenberg, Thierry Frebourg, Julien Thevenon, David Geneviève, Anne-Marie Guerrot, Andrée Delahaye-Duriez, Yline Capri, Bruno Leheup, François Lecoquierre, Florence Riccardi, Tiffany Busa, Laurent Villard, Pierre Cacciagli, Vincent Gatinois, Julien Mancini, Chantal Missirian, Lionel Van Maldergem, Massimiliano Rossi, Laurence Perrin, Catherine Vincent-Delorme, Pascale Saugier-Veber, Philippe Khau Van Kien, Gwenaël Nadeau, Annick Toutain, Alain Verloes, Sandrine Marlin, Rolph Pfundt, Elise Schaefer, Arthur Sorlin, Vincent Michaud, Christel Thauvin-Robinet, Philippe Parent, Cyril Mignot, Charles Coutton, Nicole Philip, Véronique Satre, Aude Tessier, Service de génétique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Human Genetics, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, 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 ), CHU Rouen, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Trousseau [APHP], Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), École Supérieure des Géomètres et Topographes ( ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Laboratoire de Géodésie et de Géomatique ( L2G ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Service de Cytogénétique, Centre hospitalier de Valence, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Centre Interdisciplinaire de Nanoscience de Marseille ( CINaM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), 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 [Tours], Hôpital Bretonneau-CHRU Tours, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] ( BiosTIC ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ) -Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), 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), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Bordeaux Pellegrin [Bordeaux], Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gall, Valérie, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)

Subjects
Male, 0301 basic medicine, 030105 genetics & heredity, medicine.disease_cause, Bioinformatics, Intellectual disability, Child, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Mutation, Middle Aged, KBG syndrome, Phenotype, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Chromosome Deletion, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Biology, Malignancy, Short stature, ANKRD11, Young Adult, 03 medical and health sciences, Intellectual Disability, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Precocious puberty, Abnormalities, Multiple, long-term prognosis, Alleles, Genetic Association Studies, Aged, Retrospective Studies, Bone Diseases, Developmental, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Tooth Abnormalities, 16q24.3 deletion, Point mutation, Facies, Infant, medicine.disease, haploinsufficiency, Repressor Proteins, Amino Acid Substitution, Autism, Chromosomes, Human, Pair 16
Abstract

Item does not contain fulltext KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39 patients affected by KBG syndrome. Among them, 19 were diagnosed after the detection of a 16q24.3 deletion encompassing the ANKRD11 gene by array CGH. In the 20 remaining patients, the clinical suspicion was confirmed by the identification of an ANKRD11 mutation by direct sequencing. We present arguments to modulate the previously reported diagnostic criteria. Macrodontia should no longer be considered a mandatory feature. KBG syndrome is compatible with autonomous life in adulthood. Autism is less frequent than previously reported. We also describe new clinical findings with a potential impact on the follow-up of patients, such as precocious puberty and a case of malignancy. Most deletions remove the 5'end or the entire coding region but never extend toward 16q telomere suggesting that distal 16q deletion could be lethal. Although ANKRD11 appears to be a major gene associated with intellectual disability, KBG syndrome remains under-diagnosed. NGS-based approaches for sequencing will improve the detection of point mutations in this gene. Broad knowledge of the clinical phenotype is essential for a correct interpretation of the molecular results. (c) 2016 Wiley Periodicals, Inc.

Published
2016

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