Dataset Information

The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients.

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 named MotorPlex 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.

SUBMITTER: Savarese M

PROVIDER: S-EPMC4932234 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients.

Savarese Marco M Di Fruscio Giuseppina G Torella Annalaura A Fiorillo Chiara C Magri Francesca F Fanin Marina M Ruggiero Lucia L Ricci Giulia G Astrea Guja G Passamano Luigia L Ruggieri Alessandra A Ronchi Dario D Tasca Giorgio G D'Amico Adele A Janssens Sandra S Farina Olimpia O Mutarelli Margherita M Marwah Veer Singh VS Garofalo Arcomaria A Giugliano Teresa T Sampaolo Simone S Del Vecchio Blanco Francesca F Esposito Gaia G Piluso Giulio G D'Ambrosio Paola P Petillo Roberta R Musumeci Olimpia O Rodolico Carmelo C Messina Sonia S Evilä Anni A Hackman Peter P Filosto Massimiliano M Di Iorio Giuseppe G Siciliano Gabriele G Mora Marina M Maggi Lorenzo L Minetti Carlo C Sacconi Sabrina S Santoro Lucio L Claes Kathleen K Vercelli Liliana L Mongini Tiziana T Ricci Enzo E Gualandi Francesca F Tupler Rossella R De Bleecker Jan J Udd Bjarne B Toscano Antonio A Moggio Maurizio M Pegoraro Elena E Bertini Enrico E Mercuri Eugenio E Angelini Corrado C Santorelli Filippo Maria FM Politano Luisa L Bruno Claudio C Comi Giacomo Pietro GP Nigro Vincenzo V

Neurology 20160608 1

<h4>Objective</h4>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.<h4>Methods</h4>We applied an NGS-based platform named MotorPlex 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 myopath ...[more]

PMID: 27281536

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Project description:Muscular dystrophies and congenital myopathies arise from specific genetic mutations causing skeletal muscle weakness that reduces quality of life. Muscle health relies on resident muscle stem cells called satellite cells, which enable life-course muscle growth, maintenance, repair and regeneration. Such tuned plasticity gradually diminishes in muscle diseases, suggesting compromised satellite cell function. A central issue however, is whether the pathogenic mutation perturbs satellite cell function directly and/or indirectly via an increasingly hostile microenvironment as disease progresses. Here, we explore the effects on satellite cell function of pathogenic mutations in genes (myopathogenes) that associate with muscle disorders, to evaluate clinical and muscle pathological hallmarks that define dysfunctional satellite cells. We deploy transcriptomic analysis and comparison between muscular dystrophies and myopathies to determine the contribution of satellite cell dysfunction using literature, expression dynamics of myopathogenes and their response to the satellite cell regulator PAX7. Our multimodal approach extends current pathological classifications to define Satellite Cell-opathies: muscle disorders in which satellite cell dysfunction contributes to pathology. Primary Satellite Cell-opathies are conditions where mutations in a myopathogene directly affect satellite cell function, such as in Progressive Congenital Myopathy with Scoliosis (MYOSCO) and Carey-Fineman-Ziter Syndrome (CFZS). Primary satellite cell-opathies are generally characterised as being congenital with general hypotonia, and specific involvement of respiratory, trunk and facial muscles, although serum CK levels are usually within the normal range. Secondary Satellite Cell-opathies have mutations in myopathogenes that affect both satellite cells and muscle fibres. Such classification aids diagnosis and predicting probable disease course, as well as informing on treatment and therapeutic development.

Dataset Information

The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients.

Objective

Methods

Results

Conclusions

Publications

The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients.

Similar Datasets

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