genetics; genomics; human genetics; neuromuscular diseases; Connectin; TTN protein, human; Humans; Connectin/genetics; DNA Copy Number Variations/genetics; Muscle, Skeletal/pathology; Mutation/genetics; Phenotype; Distal Myopathies/genetics; Distal Myopathies; DNA Copy Number Variations; Muscle, Skeletal; Mutation; Genetics (clinical)
Abstract :
[en] [en] BACKGROUND: Titinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype-phenotype associations.
METHODS: Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients' muscles and performed genotype-phenotype inheritance association study by combining the clinical and biological data of these eight families.
RESULTS: Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype-phenotype associations of titinopathies.
CONCLUSION: Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype-phenotype associations of titinopathies, mainly distal myopathy in most of the patients.
Disciplines :
Pediatrics
Author, co-author :
Perrin, Aurélien ; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France mireille.cossee@inserm.fr aurelien.perrin@ext.inserm.fr ; PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France
Métay, Corinne; Unité Fonctionnelle de Cardiogénétique et Myogénétique moléculaire et cellulaire, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier La Pitié-Salpêtrière-Charles Foix, Paris, France ; Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Savarese, Marco ; Tampere Neuromuscular Center, Folkhälsan Research Center, Helsinki, Finland
Ben Yaou, Rabah; Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Demidov, German; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tubingen, Germany
Nelson, Isabelle; Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Solé, Guilhem; CHU de Bordeaux, AOC National Reference Center for Neuromuscular Disorders, Bordeaux, France
Péréon, Yann; Department of Clinical Neurophysiology, Reference Centre for Neuromuscular Diseases AOC, Filnemus, Euro-NMD, CHU Nantes, Nantes Université, Place Alexis-Ricordeau, Nantes, France
Bertini, Enrico Silvio ; Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital, IRCCS, Rome, Italy
Fattori, Fabiana; Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital, IRCCS, Rome, Italy
D'Amico, Adele; Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital, IRCCS, Rome, Italy
Ricci, Federica; Division of Child and Adolescent Neuropsychiatry, University of Turin, Turin, Italy
Ginsberg, Mira; Department of Pediatric Neurology, Wolfson Medical Center, Holon, Israel
Seferian, Andreea; Institut I-MOTION, Hôpital Armand Trousseau, Paris, France
Boespflug-Tanguy, Odile; Institut I-MOTION, Hôpital Armand Trousseau, Paris, France ; UMR 1141, INSERM, NeuroDiderot Université Paris Cité and APHP, Neuropédiatrie, French Reference Center for Leukodystrophies, LEUKOFRANCE, Hôpital Robert Debré, Paris, France
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; Institut I-MOTION, Hôpital Armand Trousseau, Paris, France ; MDUK Oxford Neuromuscular Centre & NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
Chapon, Françoise; Département de pathologie, Centre de Compétence des Maladies Neuromusculaires, Centre Hospitalier Universitaire de Caen, Caen, France
Lagrange, Emmeline; Centre de Compétences des Maladies Neuro Musculaires, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
Gaudon, Karen; Unité Fonctionnelle de Cardiogénétique et Myogénétique moléculaire et cellulaire, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier La Pitié-Salpêtrière-Charles Foix, Paris, France
Bloch, Adrien; Unité Fonctionnelle de Cardiogénétique et Myogénétique moléculaire et cellulaire, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier La Pitié-Salpêtrière-Charles Foix, Paris, France
Ghanem, Robin; Unité Fonctionnelle de Cardiogénétique et Myogénétique moléculaire et cellulaire, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier La Pitié-Salpêtrière-Charles Foix, Paris, France
Guyant-Maréchal, Lucie; Department of Neurophysiology, Rouen University Hospital, Rouen, France
Johari, Mridul; Tampere Neuromuscular Center, Folkhälsan Research Center, Helsinki, Finland ; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia
Van Goethem, Charles; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France ; Montpellier BioInformatique pour le Diagnostic Clinique (MOBIDIC), Plateau de Médecine Moléculaire et Génomique (PMMG), CHU Montpellier, Montpellier, France
Fardeau, Michel; Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Morales, Raul Juntas; Department of Neurology, Hospital Universitario Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Genetti, Casie A; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Marttila, Minttu; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA ; HiLIFE Helsinki Institute of Life Science, Tukholmankatu 8, FI-00014, University of Helsinki, Helsinki, Finland
Koenig, Michel; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France ; PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France
Beggs, Alan H ; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Udd, Bjarne ; Tampere Neuromuscular Center, Folkhälsan Research Center, Helsinki, Finland
Bonne, Gisèle; Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
Cossée, Mireille ; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France mireille.cossee@inserm.fr aurelien.perrin@ext.inserm.fr ; PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France
French Muscular Dystrophy Association EU - European Union
Funding text :
This work was funded by AFM 21381 and 24259 grants (the French Muscular Dystrophy Association (AFM-Téléthon)); the Délégation à la Recherche Clinique et à l’Innovation du Groupement de Coopération Sanitaire de la Mission d’Enseignement, de Recherche, de Référence et d’Innovation (DRCI-GCS-MERRI) de Montpellier-Nîmes and the Solve-RD Project have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 779257. Analysis of family H was supported by Muscular Dystrophy Association (USA) grant MDA602235, Boston Children’s Hospital IDDRC Molecular Genetics Core Facility funded by P50HD105351 from the National Institutes of Health of USA, the Boston Children’s Hospital CRDC Initiative and by a sponsored research agreement with GeneDx. Some coauthors are members of the ERN NMD Network (AD'A, FF, OB-T, MS, RBY, IN, GS, YP, ESB, AS, MJ, BU, GB).
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