An integrated diagnosis strategy for congenital myopathies

PLoS One. 2013 Jun 24;8(6):e67527. doi: 10.1371/journal.pone.0067527. Print 2013.


Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Biopsy
  • DNA Mutational Analysis
  • Exome / genetics
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Muscles / pathology
  • Muscles / ultrastructure
  • Muscular Diseases / congenital*
  • Muscular Diseases / diagnosis*
  • Muscular Diseases / genetics
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA

Grants and funding

This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Centre national de la recherche scientifique (CNRS), University of Strasbourg, Collège de France and grants from ANR, GIS Institute for rare diseases and IBiSA, Association Francaise contre les myopathies, Muscular Dystrophy Association (United States of America) and the Myotubular Trust. This work was supported by the INSERM, the CNRS, University of Strasbourg, Collège de France and grants from the Agence Nationale de la Recherche (ANR, grant CM-WES), Muscular Dystrophy Association (MDA, grant 2010-52655) and Myotubular Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.