Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 3;12(10):1417.
doi: 10.3390/biom12101417.

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

Cristina Mazzaccara  1   2 , Raffaella Lombardi  3   4 , Bruno Mirra  1   2 , Ferdinando Barretta  1   2 , Maria Valeria Esposito  2 , Fabiana Uomo  1   2 , Martina Caiazza  5   6 , Emanuele Monda  5   6 , Maria Angela Losi  3 , Giuseppe Limongelli  5   6 , Valeria D'Argenio  2   7 , Giulia Frisso  1   2
Affiliations

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

Cristina Mazzaccara et al. Biomolecules. .

Abstract

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; "uncommon genes"). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype.

Keywords: cardiomyopathies; channelopathies; diagnostic sensitivity; genes panel analysis; genetic testing; inherited diseases; next-generation sequencing; uncommon genes.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Percentage of channelopathy and cardiomyopathy patients carrying pathogenic/likely pathogenic (P/LP) and unknown significant (VUS) variants, as identified using (A,B) first-level and (C,D) extended panels. Variants were classified according to ACMG guideline classification with respect to patients without a known causative gene.
Figure 2
Figure 2
Number of pathogenic/likely pathogenic (P/LP) variants and VUSs according to ACMG guidelines, identified in the patients analyzed using (A) first-level and (B) enlarged panels and divided by main and uncommon genes.
Figure 3
Figure 3
(A) Percentage and number of pathogenic or likely pathogenic variants collectively identified in the study cohort and (B) divided by main and uncommon genes according to clinical phenotype.
Figure 4
Figure 4
(A) Percentage and number of VUSs collectively identified in the study cohort and (B) divided by main and uncommon genes according to clinical phenotype.
Figure 5
Figure 5
Percentage of patients carrying pathogenic or likely pathogenic variants and VUSs collectively identified in study cohort and divided by main and uncommon genes.
See this image and copyright information in PMC

References

    1. Schaufelberger M. Cardiomyopathy and pregnancy. Heart. 2019;105:1543–1551. doi: 10.1136/heartjnl-2018-313476. - DOI - PMC - PubMed
    1. McKenna W.J., Maron B.J., Thiene G. Classification, Epidemiology, and Global Burden of Cardiomyopathies. Circ. Res. 2017;121:722–730. doi: 10.1161/CIRCRESAHA.117.309711. - DOI - PubMed
    1. Burke M.A., Cook S.A., Seidman J.G., Seidman C.E. Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy. J. Am. Coll. Cardiol. 2016;68:2871–2886. doi: 10.1016/j.jacc.2016.08.079. - DOI - PMC - PubMed
    1. Ackerman M.J., Priori S.G., Willems S., Berul C., Brugada R., Calkins H., Camm A.J., Ellinor P.T., Gollob M., Hamilton R., et al. HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. Heart Rhythm. 2011;8:1308–1339. doi: 10.1016/j.hrthm.2011.05.020. - DOI - PubMed
    1. Mazzaccara C., Mirra B., Barretta F., Lombardo B., Scudiero O., Frisso G. Sudden cardiac death in young athletes: Literature review of molecular basis. Cardiogenetics. 2020;10:8860. doi: 10.4081/cardiogenetics.2020.8860. - DOI

Publication types