5 years ago

Targeted next-generation sequencing detects novel gene–phenotype associations and expands the mutational spectrum in cardiomyopathies

Andrea Igoren Guaricci, Matteo Chiara, Delia De Santis, Rita Leonarda Musci, Sandro Sorrentino, Cinzia Forleo, Massimo Iacoviello, Graziano Pesole, Vito Marangelli, Antonino La Spada, Stefano Favale, Caterina Manzari, Anna Maria D’Erchia

by Cinzia Forleo, Anna Maria D’Erchia, Sandro Sorrentino, Caterina Manzari, Matteo Chiara, Massimo Iacoviello, Andrea Igoren Guaricci, Delia De Santis, Rita Leonarda Musci, Antonino La Spada, Vito Marangelli, Graziano Pesole, Stefano Favale

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype–phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies. A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC, was recruited for the study on the basis of more severe phenotypes and family history of cardiomyopathy and/or sudden death. We detected a total of 142 rare variants in 40 genes, and all patients were found to be carriers of at least one rare variant. Twenty-eight of the 142 rare variants were also predicted as potentially pathogenic variants and found in 26 patients. In 23 out of 38 patients, we found at least one novel potential gene–phenotype association. In particular, we detected three variants in OBSCN gene in ARVC patients, four variants in ANK2 gene and two variants in DLG1, TRPM4, and AKAP9 genes in DCM patients, two variants in PSEN2 gene and four variants in AKAP9 gene in HCM patients. Overall, our results confirmed that cardiomyopathic patients could carry multiple rare gene variants; in addition, our investigation of the genetic overlap among cardiomyopathies revealed new gene–phenotype associations. Furthermore, as our study confirms, data obtained using targeted next-generation sequencing could provide a remarkable contribution to the molecular diagnosis of cardiomyopathies, early identification of patients at risk for arrhythmia development, and better clinical management of cardiomyopathic patients.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.pone.0181842

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.