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Updated: Feb 25, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in
Cinzia Forleo1, Anna Maria D'Erchia2,3, Sandro Sorrentino1
1Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.
Insights
This study investigated genetic overlaps in cardiomyopathies, finding multiple rare variants per patient and novel gene-phenotype associations. Targeted sequencing aids molecular diagnosis and patient management for hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC).
Area of Science:
- Genetics and Molecular Biology
- Cardiology
- Genomic Medicine
Background:
- Cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), are primary myocardial diseases with significant morbidity and mortality.
- These conditions exhibit genetic heterogeneity, with rare mutations in numerous overlapping genes contributing to diverse phenotypes.
- Understanding genetic overlaps and genotype-phenotype correlations is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the genetic overlap among HCM, DCM, and ARVC phenotypes.
- To identify novel genotype-phenotype correlations in cardiomyopathies.
- To evaluate the utility of targeted next-generation sequencing for molecular diagnosis.
Main Methods:
- A custom gene panel of 115 genes associated with cardiomyopathies and channelopathies was designed.
- A cohort of 38 unrelated patients (16 DCM, 14 HCM, 8 ARVC) with severe phenotypes or family history was recruited.
- Targeted next-generation sequencing was employed to detect rare variants.
Main Results:
- A total of 142 rare variants in 40 genes were identified, with all patients carrying at least one rare variant.
- Twenty-eight potentially pathogenic variants were found in 26 patients.
- Novel potential gene-phenotype associations were identified in 23 patients, including variants in OBSCN (ARVC), ANK2, DLG1, TRPM4, AKAP9 (DCM), and PSEN2, AKAP9 (HCM).
Conclusions:
- Cardiomyopathic patients frequently carry multiple rare gene variants, highlighting genetic complexity.
- The study revealed new gene-phenotype associations, advancing understanding of cardiomyopathy genetics.
- Targeted next-generation sequencing is a valuable tool for molecular diagnosis, risk stratification, and improved clinical management of cardiomyopathies.
Abstract:
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.
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