Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy

Gene. 2016 Feb 15;577(2):227-35. doi: 10.1016/j.gene.2015.11.048. Epub 2015 Dec 2.


Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges.

Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants.

Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.

Keywords: Genetic testing; HCM; Hypertrophic cardiomyopathy; NGS; Next generations sequencing; Sarcomere.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / pathology
  • Desmosomes / genetics
  • Female
  • Genetic Loci*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Muscle Proteins / genetics*
  • Mutation Rate
  • Phenotype
  • Polymorphism, Genetic
  • Sarcomeres / metabolism*


  • Muscle Proteins