Marco Savarese1,2,3, Lorenzo Maggi4, Anna Vihola1, Per Harald Jonson1, Giorgio Tasca5, Lucia Ruggiero6, Luca Bello7, Francesca Magri8, Teresa Giugliano2,3, Annalaura Torella2,3, Anni Evilä1, Giuseppina Di Fruscio2,3, Olivier Vanakker9, Sara Gibertini4, Liliana Vercelli10, Alessandra Ruggieri4, Carlo Antozzi4, Helena Luque1, Sandra Janssens9, Maria Barbara Pasanisi4, Chiara Fiorillo11, Monika Raimondi12, Manuela Ergoli13, Luisa Politano13, Claudio Bruno14, Anna Rubegni15, Marika Pane16, Filippo M Santorelli15, Carlo Minetti11, Corrado Angelini17, Jan De Bleecker18, Maurizio Moggio19, Tiziana Mongini10, Giacomo Pietro Comi8, Lucio Santoro6, Eugenio Mercuri16, Elena Pegoraro7, Marina Mora4, Peter Hackman1, Bjarne Udd1,20, Vincenzo Nigro2,3. 1. Folkhälsan Research Center, Medicum, University of Helsinki, Helsinki, Finland. 2. Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania "Luigi Vanvitelli," Napoli, Italy. 3. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. 4. Neuromuscular Diseases and Neuroimmunology Unit, Institute for Research and Health Care Foundation Neurological Institute C. Besta, Milan, Italy. 5. Istituto di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli," Rome, Italy. 6. Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli "Federico II," Napoli, Italy. 7. Neuromuscular Center, Dipartimento di Neuroscienze, Università di Padova, Padova, Italy. 8. Centro Dino Ferrari, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione Institute for Research and Health Care Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. 9. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 10. Neuromuscular Unit, Department of Neurosciences, Rita Levi Montalcini, University of Torino, Torino, Italy. 11. Pediatric Neurology and Neuromuscular Disorders Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health; University of Genoa, Istituto G. Gaslini, Genova, Italy. 12. Clinica Moncucco, Lugano, Switzerland. 13. Dipartimento di Medicina Sperimentale, Cardiomiologia e Genetica Medica, Università degli Studi della Campania "Luigi Vanvitelli," Napoli, Italy. 14. Center of Myology and Neurodegenerative Disease, Istituto Giannina Gaslini, Genova, Italy. 15. Medicina Molecolare, Institute for Research and Health Care Fondazione Stella Maris, Pisa, Italy. 16. Department of Pediatric Neurology, Catholic University and Nemo Roma Center for Neuromuscular Disorders, Rome, Italy. 17. Fondazione Hospital S.Camillo Institute for Research and Health Care, Venezia, Italy. 18. Department of Neurology, Ghent University Hospital, Ghent, Belgium. 19. Neuromuscular and Rare Disease Unit, Dipartimento di Neuroscienze, Università degli Studi di Milano, Fondazione Institute for Research and Health Care Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. 20. Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.
Abstract
Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures: The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results: Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance: The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.
Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures: The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results: Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance: The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.
Authors: Peter Hackman; Anna Vihola; Henna Haravuori; Sylvie Marchand; Jaakko Sarparanta; Jerome De Seze; Siegfried Labeit; Christian Witt; Leena Peltonen; Isabelle Richard; Bjarne Udd Journal: Am J Hum Genet Date: 2002-07-26 Impact factor: 11.025
Authors: Ozge Ceyhan-Birsoy; Pankaj B Agrawal; Carlos Hidalgo; Klaus Schmitz-Abe; Elizabeth T DeChene; Lindsay C Swanson; Rachel Soemedi; Nasim Vasli; Susan T Iannaccone; Perry B Shieh; Natasha Shur; Jane M Dennison; Michael W Lawlor; Jocelyn Laporte; Kyriacos Markianos; William G Fairbrother; Henk Granzier; Alan H Beggs Journal: Neurology Date: 2013-08-23 Impact factor: 9.910
Authors: Virginie Carmignac; Mustafa A M Salih; Susana Quijano-Roy; Sylvie Marchand; Molham M Al Rayess; Maowia M Mukhtar; Jon A Urtizberea; Siegfried Labeit; Pascale Guicheney; France Leturcq; Mathias Gautel; Michel Fardeau; Kevin P Campbell; Isabelle Richard; Brigitte Estournet; Ana Ferreiro Journal: Ann Neurol Date: 2007-04 Impact factor: 10.422
Authors: Rocío N Villar-Quiles; Fabio Catervi; Eva Cabet; Raul Juntas-Morales; Casie A Genetti; Teresa Gidaro; Asuman Koparir; Adnan Yüksel; Sandra Coppens; Nicolas Deconinck; Emma Pierce-Hoffman; Xavière Lornage; Julien Durigneux; Jocelyn Laporte; John Rendu; Norma B Romero; Alan H Beggs; Laurent Servais; Mireille Cossée; Montse Olivé; Johann Böhm; Isabelle Duband-Goulet; Ana Ferreiro Journal: Ann Neurol Date: 2019-12-27 Impact factor: 10.422