The genetic basis of undiagnosed muscular dystrophies and myopathies

Marco Savarese, Giuseppina Di Fruscio, Annalaura Torella, Chiara Fiorillo, Francesca Magri, Marina Fanin, Lucia Ruggiero, Giulia Ricci, Guja Astrea, Luigia Passamano, Alessandra Ruggieri, Dario Ronchi, Giorgio Tasca, Adele D'Amico, Sandra Janssens, Olimpia Farina, Margherita Mutarelli, Veer Singh Marwah, Arcomaria Garofalo, Teresa GiuglianoSimone Sanpaolo, Francesca Del Vecchio Blanco, Gaia Esposito, Giulio Piluso, Paola D'Ambrosio, Roberta Petillo, Olimpia Musumeci, Carmelo Rodolico, Sonia Messina, Anni Evilä, Peter Hackman, Massimiliano Filosto, Giuseppe Di Iorio, Gabriele Siciliano, Marina Mora, Lorenzo Maggi, Carlo Minetti, Sabrina Sacconi, Lucio Santoro, Kathleen Claes, Liliana Vercelli, Tiziana Mongini, Enzo Ricci, Francesca Gualandi, Rossella Tupler, Jan De Bleecker, Bjarne Udd, Antonio Toscano, Maurizio Moggio, Elena Pegoraro, Enrico Bertini, Eugenio Mercuri, Corrado Angelini, Filippo Maria Santorelli, Luisa Politano, Claudio Bruno, Giacomo Pietro Comi, Vincenzo Nigro

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform namedMotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30%of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.

Original languageEnglish
Pages (from-to)71-76
Number of pages6
JournalNeurology
Volume87
Issue number1
DOIs
Publication statusPublished - Jul 5 2016

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Muscular Dystrophies
Muscular Diseases
Limb-Girdle Muscular Dystrophies
Myotonia Congenita
Genes
Molecular Pathology
Workflow
DNA
Phenotype
Sensitivity and Specificity
Muscles

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Savarese, M., Di Fruscio, G., Torella, A., Fiorillo, C., Magri, F., Fanin, M., ... Nigro, V. (2016). The genetic basis of undiagnosed muscular dystrophies and myopathies. Neurology, 87(1), 71-76. https://doi.org/10.1212/WNL.0000000000002800

The genetic basis of undiagnosed muscular dystrophies and myopathies. / Savarese, Marco; Di Fruscio, Giuseppina; Torella, Annalaura; Fiorillo, Chiara; Magri, Francesca; Fanin, Marina; Ruggiero, Lucia; Ricci, Giulia; Astrea, Guja; Passamano, Luigia; Ruggieri, Alessandra; Ronchi, Dario; Tasca, Giorgio; D'Amico, Adele; Janssens, Sandra; Farina, Olimpia; Mutarelli, Margherita; Marwah, Veer Singh; Garofalo, Arcomaria; Giugliano, Teresa; Sanpaolo, Simone; Del Vecchio Blanco, Francesca; Esposito, Gaia; Piluso, Giulio; D'Ambrosio, Paola; Petillo, Roberta; Musumeci, Olimpia; Rodolico, Carmelo; Messina, Sonia; Evilä, Anni; Hackman, Peter; Filosto, Massimiliano; Di Iorio, Giuseppe; Siciliano, Gabriele; Mora, Marina; Maggi, Lorenzo; Minetti, Carlo; Sacconi, Sabrina; Santoro, Lucio; Claes, Kathleen; Vercelli, Liliana; Mongini, Tiziana; Ricci, Enzo; Gualandi, Francesca; Tupler, Rossella; De Bleecker, Jan; Udd, Bjarne; Toscano, Antonio; Moggio, Maurizio; Pegoraro, Elena; Bertini, Enrico; Mercuri, Eugenio; Angelini, Corrado; Santorelli, Filippo Maria; Politano, Luisa; Bruno, Claudio; Comi, Giacomo Pietro; Nigro, Vincenzo.

In: Neurology, Vol. 87, No. 1, 05.07.2016, p. 71-76.

Research output: Contribution to journalArticle

Savarese, M, Di Fruscio, G, Torella, A, Fiorillo, C, Magri, F, Fanin, M, Ruggiero, L, Ricci, G, Astrea, G, Passamano, L, Ruggieri, A, Ronchi, D, Tasca, G, D'Amico, A, Janssens, S, Farina, O, Mutarelli, M, Marwah, VS, Garofalo, A, Giugliano, T, Sanpaolo, S, Del Vecchio Blanco, F, Esposito, G, Piluso, G, D'Ambrosio, P, Petillo, R, Musumeci, O, Rodolico, C, Messina, S, Evilä, A, Hackman, P, Filosto, M, Di Iorio, G, Siciliano, G, Mora, M, Maggi, L, Minetti, C, Sacconi, S, Santoro, L, Claes, K, Vercelli, L, Mongini, T, Ricci, E, Gualandi, F, Tupler, R, De Bleecker, J, Udd, B, Toscano, A, Moggio, M, Pegoraro, E, Bertini, E, Mercuri, E, Angelini, C, Santorelli, FM, Politano, L, Bruno, C, Comi, GP & Nigro, V 2016, 'The genetic basis of undiagnosed muscular dystrophies and myopathies', Neurology, vol. 87, no. 1, pp. 71-76. https://doi.org/10.1212/WNL.0000000000002800
Savarese M, Di Fruscio G, Torella A, Fiorillo C, Magri F, Fanin M et al. The genetic basis of undiagnosed muscular dystrophies and myopathies. Neurology. 2016 Jul 5;87(1):71-76. https://doi.org/10.1212/WNL.0000000000002800
Savarese, Marco ; Di Fruscio, Giuseppina ; Torella, Annalaura ; Fiorillo, Chiara ; Magri, Francesca ; Fanin, Marina ; Ruggiero, Lucia ; Ricci, Giulia ; Astrea, Guja ; Passamano, Luigia ; Ruggieri, Alessandra ; Ronchi, Dario ; Tasca, Giorgio ; D'Amico, Adele ; Janssens, Sandra ; Farina, Olimpia ; Mutarelli, Margherita ; Marwah, Veer Singh ; Garofalo, Arcomaria ; Giugliano, Teresa ; Sanpaolo, Simone ; Del Vecchio Blanco, Francesca ; Esposito, Gaia ; Piluso, Giulio ; D'Ambrosio, Paola ; Petillo, Roberta ; Musumeci, Olimpia ; Rodolico, Carmelo ; Messina, Sonia ; Evilä, Anni ; Hackman, Peter ; Filosto, Massimiliano ; Di Iorio, Giuseppe ; Siciliano, Gabriele ; Mora, Marina ; Maggi, Lorenzo ; Minetti, Carlo ; Sacconi, Sabrina ; Santoro, Lucio ; Claes, Kathleen ; Vercelli, Liliana ; Mongini, Tiziana ; Ricci, Enzo ; Gualandi, Francesca ; Tupler, Rossella ; De Bleecker, Jan ; Udd, Bjarne ; Toscano, Antonio ; Moggio, Maurizio ; Pegoraro, Elena ; Bertini, Enrico ; Mercuri, Eugenio ; Angelini, Corrado ; Santorelli, Filippo Maria ; Politano, Luisa ; Bruno, Claudio ; Comi, Giacomo Pietro ; Nigro, Vincenzo. / The genetic basis of undiagnosed muscular dystrophies and myopathies. In: Neurology. 2016 ; Vol. 87, No. 1. pp. 71-76.
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abstract = "Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform namedMotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3{\%}). A further 160 patients (31.7{\%}) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30{\%}of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.",
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AU - Savarese, Marco

AU - Di Fruscio, Giuseppina

AU - Torella, Annalaura

AU - Fiorillo, Chiara

AU - Magri, Francesca

AU - Fanin, Marina

AU - Ruggiero, Lucia

AU - Ricci, Giulia

AU - Astrea, Guja

AU - Passamano, Luigia

AU - Ruggieri, Alessandra

AU - Ronchi, Dario

AU - Tasca, Giorgio

AU - D'Amico, Adele

AU - Janssens, Sandra

AU - Farina, Olimpia

AU - Mutarelli, Margherita

AU - Marwah, Veer Singh

AU - Garofalo, Arcomaria

AU - Giugliano, Teresa

AU - Sanpaolo, Simone

AU - Del Vecchio Blanco, Francesca

AU - Esposito, Gaia

AU - Piluso, Giulio

AU - D'Ambrosio, Paola

AU - Petillo, Roberta

AU - Musumeci, Olimpia

AU - Rodolico, Carmelo

AU - Messina, Sonia

AU - Evilä, Anni

AU - Hackman, Peter

AU - Filosto, Massimiliano

AU - Di Iorio, Giuseppe

AU - Siciliano, Gabriele

AU - Mora, Marina

AU - Maggi, Lorenzo

AU - Minetti, Carlo

AU - Sacconi, Sabrina

AU - Santoro, Lucio

AU - Claes, Kathleen

AU - Vercelli, Liliana

AU - Mongini, Tiziana

AU - Ricci, Enzo

AU - Gualandi, Francesca

AU - Tupler, Rossella

AU - De Bleecker, Jan

AU - Udd, Bjarne

AU - Toscano, Antonio

AU - Moggio, Maurizio

AU - Pegoraro, Elena

AU - Bertini, Enrico

AU - Mercuri, Eugenio

AU - Angelini, Corrado

AU - Santorelli, Filippo Maria

AU - Politano, Luisa

AU - Bruno, Claudio

AU - Comi, Giacomo Pietro

AU - Nigro, Vincenzo

PY - 2016/7/5

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N2 - Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform namedMotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30%of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.

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