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Original research
Titin copy number variations associated with dominant inherited phenotypes
  1. Aurélien Perrin1,2,
  2. Corinne Métay3,4,
  3. Marco Savarese5,
  4. Rabah Ben Yaou4,
  5. German Demidov6,
  6. Isabelle Nelson4,
  7. Guilhem Solé7,
  8. Yann Péréon8,
  9. Enrico Silvio Bertini9,
  10. Fabiana Fattori9,
  11. Adele D'Amico9,
  12. Federica Ricci10,
  13. Mira Ginsberg11,
  14. Andreea Seferian12,
  15. Odile Boespflug-Tanguy12,13,
  16. Laurent Servais12,14,15,
  17. Françoise Chapon16,
  18. Emmeline Lagrange17,
  19. Karen Gaudon3,
  20. Adrien Bloch3,
  21. Robin Ghanem3,
  22. Lucie Guyant-Maréchal18,
  23. Mridul Johari5,19,
  24. Charles Van Goethem1,20,
  25. Michel Fardeau4,
  26. Raul Juntas Morales21,
  27. Casie A Genetti22,
  28. Minttu Marttila22,23,
  29. Michel Koenig1,2,
  30. Alan H Beggs22,
  31. Bjarne Udd5,
  32. Gisèle Bonne4,
  33. Mireille Cossée1,2
  1. 1 Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
  2. 2 PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France
  3. 3 Unité Fonctionnelle de Cardiogénétique et Myogénétique moléculaire et cellulaire, Centre de Génétique Moléculaire et Chromosomique, Groupe Hospitalier La Pitié-Salpêtrière-Charles Foix, Paris, France
  4. 4 Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
  5. 5 Tampere Neuromuscular Center, Folkhälsan Research Center, Helsinki, Finland
  6. 6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tubingen, Germany
  7. 7 CHU de Bordeaux, AOC National Reference Center for Neuromuscular Disorders, Bordeaux, France
  8. 8 Department of Clinical Neurophysiology, Reference Centre for Neuromuscular Diseases AOC, Filnemus, Euro-NMD, CHU Nantes, Nantes Université, Place Alexis-Ricordeau, Nantes, France
  9. 9 Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital, IRCCS, Rome, Italy
  10. 10 Division of Child and Adolescent Neuropsychiatry, University of Turin, Turin, Italy
  11. 11 Department of Pediatric Neurology, Wolfson Medical Center, Holon, Israel
  12. 12 Institut I-MOTION, Hôpital Armand Trousseau, Paris, France
  13. 13 UMR 1141, INSERM, NeuroDiderot Université Paris Cité and APHP, Neuropédiatrie, French Reference Center for Leukodystrophies, LEUKOFRANCE, Hôpital Robert Debré, Paris, France
  14. 14 MDUK Oxford Neuromuscular Centre & NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
  15. 15 Neuromuscular Reference Center, Division of Paediatrics, University and Hospital University of Liège, Liège, Belgium
  16. 16 Département de pathologie, Centre de Compétence des Maladies Neuromusculaires, Centre Hospitalier Universitaire de Caen, Caen, France
  17. 17 Centre de Compétences des Maladies Neuro Musculaires, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
  18. 18 Department of Neurophysiology, Rouen University Hospital, Rouen, France
  19. 19 Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia
  20. 20 Montpellier BioInformatique pour le Diagnostic Clinique (MOBIDIC), Plateau de Médecine Moléculaire et Génomique (PMMG), CHU Montpellier, Montpellier, France
  21. 21 Department of Neurology, Hospital Universitario Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  22. 22 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  23. 23 HiLIFE Helsinki Institute of Life Science, Tukholmankatu 8, FI-00014, University of Helsinki, Helsinki, Finland
  1. Correspondence to Dr Mireille Cossée, Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France; mireille.cossee{at}; Dr Aurélien Perrin, Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France; aurelien.perrin{at}


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.

  • genetics
  • genomics
  • human genetics
  • neuromuscular diseases

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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  • Twitter @mriduljohari, @BonneGisele

  • AP and MC contributed equally.

  • Correction notice This article has been corrected since it was published online first. The name of one of the authors has been amended.

  • Contributors AP, CM, MS, AB, BU, GB and MC contributed to the conception and design of the study. All authors contributed to the acquisition and analysis of data. AP, CM, MS, RBY, CVG, BU and MC contributed to drafting a significant portion of the manuscript or figures. MC and AP are the guarantors of this study.

  • Funding 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).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.