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 Evilä, 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 journalArticle

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.

Original languageEnglish
Pages (from-to)557-565
Number of pages9
JournalJAMA Neurology
Volume75
Issue number5
DOIs
Publication statusPublished - May 1 2018

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Connectin
Muscular Diseases
Genes
Mutation
Myotonia Congenita
Distal Myopathies
Messenger RNA
Inborn Genetic Diseases
Workflow
Muscular Dystrophies
Computational Biology
Age of Onset
Skeletal Muscle
Proteins
Outcome Assessment (Health Care)

Cite this

Savarese, M., Maggi, L., Vihola, A., Jonson, P. H., Tasca, G., Ruggiero, L., ... Nigro, V. (2018). Interpreting Genetic Variants in Titin in Patients With Muscle Disorders. JAMA Neurology, 75(5), 557-565. https://doi.org/10.1001/jamaneurol.2017.4899

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

In: JAMA Neurology, Vol. 75, No. 5, 01.05.2018, p. 557-565.

Research output: Contribution to journalArticle

Savarese, M, Maggi, L, Vihola, A, Jonson, PH, Tasca, G, Ruggiero, L, Bello, L, Magri, F, Giugliano, T, Torella, A, Evilä, A, Di Fruscio, G, Vanakker, O, Gibertini, S, Vercelli, L, Ruggieri, A, Antozzi, C, Luque, H, Janssens, S, Pasanisi, MB, Fiorillo, C, Raimondi, M, Ergoli, M, Politano, L, Bruno, C, Rubegni, A, Pane, M, Santorelli, FM, Minetti, C, Angelini, C, De Bleecker, J, Moggio, M, Mongini, T, Comi, GP, Santoro, L, Mercuri, E, Pegoraro, E, Mora, M, Hackman, P, Udd, B & Nigro, V 2018, 'Interpreting Genetic Variants in Titin in Patients With Muscle Disorders', JAMA Neurology, vol. 75, no. 5, pp. 557-565. https://doi.org/10.1001/jamaneurol.2017.4899
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 May 1;75(5):557-565. https://doi.org/10.1001/jamaneurol.2017.4899
Savarese, Marco ; Maggi, Lorenzo ; Vihola, Anna ; Jonson, Per Harald ; Tasca, Giorgio ; Ruggiero, Lucia ; Bello, Luca ; Magri, Francesca ; Giugliano, Teresa ; Torella, Annalaura ; Evilä, Anni ; Di Fruscio, Giuseppina ; Vanakker, Olivier ; Gibertini, Sara ; Vercelli, Liliana ; Ruggieri, Alessandra ; Antozzi, Carlo ; Luque, Helena ; Janssens, Sandra ; Pasanisi, Maria Barbara ; Fiorillo, Chiara ; Raimondi, Monika ; Ergoli, Manuela ; Politano, Luisa ; Bruno, Claudio ; Rubegni, Anna ; Pane, Marika ; Santorelli, Filippo M ; Minetti, Carlo ; Angelini, Corrado ; De Bleecker, Jan ; Moggio, Maurizio ; Mongini, Tiziana ; Comi, Giacomo Pietro ; Santoro, Lucio ; Mercuri, Eugenio ; Pegoraro, Elena ; Mora, Marina ; Hackman, Peter ; Udd, Bjarne ; Nigro, Vincenzo. / Interpreting Genetic Variants in Titin in Patients With Muscle Disorders. In: JAMA Neurology. 2018 ; Vol. 75, No. 5. pp. 557-565.
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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 = "Marco Savarese and Lorenzo Maggi and Anna Vihola and Jonson, {Per Harald} and Giorgio Tasca and Lucia Ruggiero and Luca Bello and Francesca Magri and Teresa Giugliano and Annalaura Torella and Anni Evil{\"a} and {Di Fruscio}, Giuseppina and Olivier Vanakker and Sara Gibertini and Liliana Vercelli and Alessandra Ruggieri and Carlo Antozzi and Helena Luque and Sandra Janssens and Pasanisi, {Maria Barbara} and Chiara Fiorillo and Monika Raimondi and Manuela Ergoli and Luisa Politano and Claudio Bruno and Anna Rubegni and Marika Pane and Santorelli, {Filippo M} and Carlo Minetti and Corrado Angelini and {De Bleecker}, Jan and Maurizio Moggio and Tiziana Mongini and Comi, {Giacomo Pietro} and Lucio Santoro and Eugenio Mercuri and Elena Pegoraro and Marina Mora and Peter Hackman and Bjarne Udd and Vincenzo Nigro",
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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 - Evilä, 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 - 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 - De Bleecker, Jan

AU - Moggio, Maurizio

AU - Mongini, Tiziana

AU - Comi, Giacomo Pietro

AU - Santoro, Lucio

AU - Mercuri, Eugenio

AU - Pegoraro, Elena

AU - Mora, Marina

AU - Hackman, Peter

AU - Udd, Bjarne

AU - Nigro, Vincenzo

PY - 2018/5/1

Y1 - 2018/5/1

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.

U2 - 10.1001/jamaneurol.2017.4899

DO - 10.1001/jamaneurol.2017.4899

M3 - Article

C2 - 29435569

VL - 75

SP - 557

EP - 565

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 5

ER -