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 Giugliano; Simone 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

doi:10.1212/WNL.0000000000002800

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

Fondazione Stella Maris

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	71-76
Number of pages	6
Journal	Neurology
Volume	87
Issue number	1
DOIs	https://doi.org/10.1212/WNL.0000000000002800
Publication status	Published - Jul 5 2016

ASJC Scopus subject areas

Clinical Neurology

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10.1212/WNL.0000000000002800

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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, V. S., Garofalo, A., ... 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 journal › Article › peer-review

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, 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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title = "The genetic basis of undiagnosed muscular dystrophies and myopathies",

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.",

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

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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

Y1 - 2016/7/5

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.

AB - 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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The genetic basis of undiagnosed muscular dystrophies and myopathies

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