Interpreting genetic variants in titin in patients with muscle disorders

Marco Savarese, Lorenzo Maggi, Anna Vihola, Per Harald Jonson, Giorgio Tasca, Lucia Ruggiero, Luca Bello, Francesca Magri, Teresa Giugliano, Annalaura Torella, Anni Evila, Giuseppina Di Fruscio, Olivier Vanakker, Sara Gibertini, Liliana Vercelli, Alessandra Ruggieri, Carlo Antozzi, Helena Luque, Sandra Janssens, Maria Barbara PasanisiChiara Fiorillo, Monika Raimondi, Manuela Ergoli, Luisa Politano, Claudio Bruno, Anna Rubegni, Marika Pane, Filippo M. Santorelli, Carlo Minetti, Corrado Angelini, Jan De Bleecker, Maurizio Moggio, Tiziana Mongini, Giacomo Pietro Comi, Lucio Santoro, Eugenio Mercuri, Elena Pegoraro, Marina Mora, Peter Hackman, Bjarne Udd, Vincenzo Nigro

Research output: Contribution to journalArticlepeer-review


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, congenitalmyopathy, 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 congenitalmyopathy and 2 (50%) had a slowly progressive distalmyopathy 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.

Original languageEnglish
Pages (from-to)557-565
Number of pages9
JournalJAMA Neurology
Issue number5
Publication statusPublished - May 1 2018

ASJC Scopus subject areas

  • Clinical Neurology


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