Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

Hum Genomics. 2018 Jul 3;12(1):34. doi: 10.1186/s40246-018-0167-1.


Background: Limb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis.

Methods: Whole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis.

Results: Genetic diagnosis was possible in 68.5% of cases. On average, 36.3 rare variants in genes associated with various muscle diseases per patient were found that could relate to the clinical phenotype. The putative causative mutations were mostly in LGMD-associated genes, but also in genes not included in the current LGMD classification (DMD, COL6A2, and COL6A3). In three patients, mutations in two genes were suggested as the joint cause of the disease (CAPN3+MYH7, COL6A3+CACNA1S, DYSF+MYH7). Moreover, a variety of phenotype-influencing variants were postulated, including in patients with an identified already known primary pathogenic mutation.

Conclusions: We hypothesize that LGMD could be better described as oligogenic disorders in which dominant clinical presentation can result from the combined effect of mutations in a set of genes. In this view, the inter- and intrafamilial variability could reflect a specific genetic background and the presence of sets of phenotype-influencing or co-causative mutations in genes that either interact with the known LGMD-associated genes or are a part of the same pathways or structures.

Keywords: Exome; LGMD; Limb-girdle muscular dystrophy; NGS; Next generation sequencing; Skeletal muscle; WES.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Calcium Channels / genetics
  • Calcium Channels, L-Type
  • Calpain / genetics*
  • Cardiac Myosins / genetics*
  • Child
  • Child, Preschool
  • Collagen Type VI / genetics
  • Dysferlin / genetics*
  • Exome / genetics
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Muscle Proteins / genetics*
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Mutation / genetics
  • Myosin Heavy Chains / genetics*
  • Phenotype
  • Poland
  • Sequence Analysis, DNA
  • Young Adult


  • CACNA1S protein, human
  • COL6A3 protein, human
  • Calcium Channels
  • Calcium Channels, L-Type
  • Collagen Type VI
  • DYSF protein, human
  • Dysferlin
  • MYH7 protein, human
  • Muscle Proteins
  • CAPN3 protein, human
  • Calpain
  • Cardiac Myosins
  • Myosin Heavy Chains