Interpreting genetic variants in titin in patients with muscle disorders

M. Savarese, L. Maggi, A. Vihola, P.H. Jonson, G. Tasca, L. Ruggiero, L. Bello, F. Magri, T. Giugliano, A. Torella, A. Evila, G. Di Fruscio, O. Vanakker, S. Gibertini, L. Vercelli, A. Ruggieri, C. Antozzi, H. Luque, S. Janssens, M.B. PasanisiC. Fiorillo, M. Raimondi, M. Ergoli, L. Politano, C. Bruno, A. Rubegni, M. Pane, F.M. Santorelli, C. Minetti, C. Angelini, J. De Bleecker, M. Moggio, T. Mongini, G.P. Comi, L. Santoro, E. Mercuri, E. Pegoraro, M. Mora, P. Hackman, B. Udd, V. 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, 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. © 2018 American Medical Association. All rights reserved.
Original languageEnglish
Pages (from-to)557-565
Number of pages9
JournalJAMA Neurology
Volume75
Issue number5
DOIs
Publication statusPublished - 2018

Fingerprint

Connectin
Muscular Diseases
Genes
Mutation
Messenger RNA
Inborn Genetic Diseases
Workflow
Muscular Dystrophies
American Medical Association
Computational Biology
Age of Onset
Skeletal Muscle
Proteins

Keywords

  • connectin
  • genomic DNA
  • messenger RNA, adolescent
  • adult
  • Article
  • case study
  • child
  • clinical article
  • cohort analysis
  • controlled study
  • distal myopathy
  • female
  • gene mutation
  • genetic variability
  • heterozygosity
  • human
  • human tissue
  • infant
  • male
  • middle aged
  • missense mutation
  • muscle disease
  • muscular dystrophy
  • next generation sequencing
  • priority journal
  • Sanger sequencing
  • TTN gene

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, M.; Maggi, L.; Vihola, A.; Jonson, P.H.; Tasca, G.; Ruggiero, L.; Bello, L.; Magri, F.; Giugliano, T.; Torella, A.; Evila, A.; Di Fruscio, G.; Vanakker, O.; Gibertini, S.; Vercelli, L.; Ruggieri, A.; Antozzi, C.; Luque, H.; Janssens, S.; Pasanisi, M.B.; Fiorillo, C.; Raimondi, M.; Ergoli, M.; Politano, L.; Bruno, C.; Rubegni, A.; Pane, M.; Santorelli, F.M.; Minetti, C.; Angelini, C.; De Bleecker, J.; Moggio, M.; Mongini, T.; Comi, G.P.; Santoro, L.; Mercuri, E.; Pegoraro, E.; Mora, M.; Hackman, P.; Udd, B.; Nigro, V.

In: JAMA Neurology, Vol. 75, No. 5, 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, Evila, 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, P.H. ; Tasca, G. ; Ruggiero, L. ; Bello, L. ; Magri, F. ; Giugliano, T. ; Torella, A. ; Evila, A. ; Di Fruscio, G. ; Vanakker, O. ; Gibertini, S. ; Vercelli, L. ; Ruggieri, A. ; Antozzi, C. ; Luque, H. ; Janssens, S. ; Pasanisi, M.B. ; Fiorillo, C. ; Raimondi, M. ; Ergoli, M. ; Politano, L. ; Bruno, C. ; Rubegni, A. ; Pane, M. ; Santorelli, F.M. ; Minetti, C. ; Angelini, C. ; De Bleecker, J. ; Moggio, M. ; Mongini, T. ; Comi, G.P. ; Santoro, L. ; Mercuri, E. ; Pegoraro, E. ; Mora, M. ; Hackman, P. ; Udd, B. ; Nigro, V. / 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, 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. {\circledC} 2018 American Medical Association. All rights reserved.",
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TY - JOUR

T1 - Interpreting genetic variants in titin in patients with muscle disorders

AU - Savarese, M.

AU - Maggi, L.

AU - Vihola, A.

AU - Jonson, P.H.

AU - Tasca, G.

AU - Ruggiero, L.

AU - Bello, L.

AU - Magri, F.

AU - Giugliano, T.

AU - Torella, A.

AU - Evila, A.

AU - Di Fruscio, G.

AU - Vanakker, O.

AU - Gibertini, S.

AU - Vercelli, L.

AU - Ruggieri, A.

AU - Antozzi, C.

AU - Luque, H.

AU - Janssens, S.

AU - Pasanisi, M.B.

AU - Fiorillo, C.

AU - Raimondi, M.

AU - Ergoli, M.

AU - Politano, L.

AU - Bruno, C.

AU - Rubegni, A.

AU - Pane, M.

AU - Santorelli, F.M.

AU - Minetti, C.

AU - Angelini, C.

AU - De Bleecker, J.

AU - Moggio, M.

AU - Mongini, T.

AU - Comi, G.P.

AU - Santoro, L.

AU - Mercuri, E.

AU - Pegoraro, E.

AU - Mora, M.

AU - Hackman, P.

AU - Udd, B.

AU - Nigro, V.

N1 - cited By 2

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, 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. © 2018 American Medical Association. All rights reserved.

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, 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. © 2018 American Medical Association. All rights reserved.

KW - connectin

KW - genomic DNA

KW - messenger RNA, adolescent

KW - adult

KW - Article

KW - case study

KW - child

KW - clinical article

KW - cohort analysis

KW - controlled study

KW - distal myopathy

KW - female

KW - gene mutation

KW - genetic variability

KW - heterozygosity

KW - human

KW - human tissue

KW - infant

KW - male

KW - middle aged

KW - missense mutation

KW - muscle disease

KW - muscular dystrophy

KW - next generation sequencing

KW - priority journal

KW - Sanger sequencing

KW - TTN gene

U2 - 10.1001/jamaneurol.2017.4899

DO - 10.1001/jamaneurol.2017.4899

M3 - Article

VL - 75

SP - 557

EP - 565

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

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