TY - JOUR
T1 - Interpreting Genetic Variants in Titin in Patients With Muscle Disorders.
AU - Savarese, Marco
AU - Maggi, Lorenzo
AU - Vihola, Anna
AU - Jonson, Per Harald
AU - Tasca, Giorgio
AU - Ruggiero, Lucia
AU - Bello, Luca
AU - Magri, Francesca
AU - Giugliano, Teresa
AU - Torella, Annalaura
AU - Evila, Anni
AU - Di Fruscio, Giuseppina
AU - Vanakker, Olivier
AU - Gibertini, Sara
AU - Vercelli, Liliana
AU - Ruggieri, Alessandra
AU - Antozzi, Carlo
AU - Luque, Helena
AU - Janssens, Sandra
AU - Pasanisi, Maria Barbara
AU - Fiorillo, Chiara
AU - Fiorillo, Claudio
AU - Raimondi, Monika
AU - Ergoli, Manuela
AU - Politano, Luisa
AU - Bruno, Claudio
AU - Rubegni, Anna
AU - Pane, Marika
AU - Santorelli, Filippo M.
AU - Minetti, Carlo
AU - Angelini, Corrado
AU - Angelini, Carlo
AU - De Bleecker, Jan
AU - Moggio, Maurizio
AU - Mongini, Tiziana
AU - Comi, Giacomo Pietro
AU - Santoro, Lucio
AU - Mercuri, Eugenio Maria
AU - Pegoraro, Elena
AU - Mora, Marina
AU - Hackman, Peter
AU - Udd, Bjarne
AU - Nigro, Vincenzo
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - muscle disorders
KW - muscle disorders
UR - http://hdl.handle.net/10807/125531
U2 - 10.1001/jamaneurol.2017.4899
DO - 10.1001/jamaneurol.2017.4899
M3 - Article
SN - 2168-6149
SP - 557
EP - 565
JO - JAMA Neurology
JF - JAMA Neurology
ER -