Advanced search
1 file | 3.17 MB

Interpreting genetic variants in titin in patients with muscle disorders

(2018) JAMA NEUROLOGY. 75(5). p.557-565
Author
Organization
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.
Keywords
TIBIAL MUSCULAR-DYSTROPHY, C-TERMINAL TITIN, TRUNCATING MUTATIONS, DISTAL MYOPATHY, TTN, CARDIOMYOPATHY, TITINOPATHY, PHENOTYPES, SEQUENCE, ISOFORM

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 3.17 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Savarese, Marco, Lorenzo Maggi, Anna Vihola, Per Harald Jonson, Giorgio Tasca, Lucia Ruggiero, Luca Bello, et al. 2018. “Interpreting Genetic Variants in Titin in Patients with Muscle Disorders.” Jama Neurology 75 (5): 557–565.
APA
Savarese, Marco, Maggi, L., Vihola, A., Jonson, P. H., Tasca, G., Ruggiero, L., Bello, L., et al. (2018). Interpreting genetic variants in titin in patients with muscle disorders. JAMA NEUROLOGY, 75(5), 557–565.
Vancouver
1.
Savarese M, Maggi L, Vihola A, Jonson PH, Tasca G, Ruggiero L, et al. Interpreting genetic variants in titin in patients with muscle disorders. JAMA NEUROLOGY. 2018;75(5):557–65.
MLA
Savarese, Marco, Lorenzo Maggi, Anna Vihola, et al. “Interpreting Genetic Variants in Titin in Patients with Muscle Disorders.” JAMA NEUROLOGY 75.5 (2018): 557–565. Print.
@article{8560539,
  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.},
  author       = {Savarese, Marco and Maggi, Lorenzo and Vihola, Anna and Jonson, Per Harald and Tasca, Giorgio and Ruggiero, Lucia and Bello, Luca and Magri, Francesca and Giugliano, Teresa and Torella, Annalaura and Evil{\"a}, Anni and Di Fruscio, Giuseppina and Vanakker, Olivier and Gibertini, Sara and Vercelli, Liliana and Ruggieri, Alessandra and Antozzi, Carlo and Luque, Helena and Janssens, Sandra and Pasanisi, Maria Barbara and Fiorillo, Chiara and Raimondi, Monika and Ergoli, Manuela and Politano, Luisa and Bruno, Claudio and Rubegni, Anna and Pane, Marika and Santorelli, Filippo M and Minetti, Carlo and Angelini, Corrado and De Bleecker, Jan and Moggio, Maurizio and Mongini, Tiziana and Comi, Giacomo Pietro and Santoro, Lucio and Mercuri, Eugenio and Pegoraro, Elena and Mora, Marina and Hackman, Peter and Udd, Bjarne and Nigro, Vincenzo},
  issn         = {2168-6149},
  journal      = {JAMA NEUROLOGY},
  keyword      = {TIBIAL MUSCULAR-DYSTROPHY,C-TERMINAL TITIN,TRUNCATING MUTATIONS,DISTAL MYOPATHY,TTN,CARDIOMYOPATHY,TITINOPATHY,PHENOTYPES,SEQUENCE,ISOFORM},
  language     = {eng},
  number       = {5},
  pages        = {557--565},
  title        = {Interpreting genetic variants in titin in patients with muscle disorders},
  url          = {http://dx.doi.org/10.1001/jamaneurol.2017.4899},
  volume       = {75},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: