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
Multicenter Study
. 2021 May 4;10(9):e017731.
doi: 10.1161/JAHA.120.017731. Epub 2021 Apr 28.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study

Stephanie M Ware  1 , James D Wilkinson  2 , Muhammad Tariq  3 , Jeffrey A Schubert  1 , Arthi Sridhar  1 , Steven D Colan  4 , Ling Shi  5 , Charles E Canter  6 , Daphne T Hsu  7 , Steven A Webber  2 , Debra A Dodd  2 , Melanie D Everitt  8 , Paul F Kantor  9 , Linda J Addonizio  10 , John L Jefferies  11 , Joseph W Rossano  12 , Elfriede Pahl  13 , Paolo Rusconi  14 , Wendy K Chung  10 , Teresa Lee  10 , Jeffrey A Towbin  11 , Ashwin K Lal  15 , Surbhi Bhatnagar  16 , Bruce Aronow  16 , Phillip J Dexheimer  16 , Lisa J Martin  16 , Erin M Miller  16 , Lynn A Sleeper  4 , Hiedy Razoky  17 , Jason Czachor  17 , Steven E Lipshultz  18   19 ; Pediatric Cardiomyopathy Registry Study Group
Affiliations
Multicenter Study

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study

Stephanie M Ware et al. J Am Heart Assoc. .

Erratum in

Abstract

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

Keywords: exome; heart failure; infant; molecular; mutation.

PubMed Disclaimer

Conflict of interest statement

Dr Steven E. Lipshultz is a consultant for Tenaya Therapeutics, Bayer, and on an advisory board for Myokardia.

Figures

Figure 1
Figure 1. Characteristics of 152 children in the pediatric cardiomyopathy genes study.
A, Distribution of cardiomyopathy phenotypes; B, Median (interquartile range) age at cardiomyopathy diagnosis by sex and cardiomyopathy phenotype. DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; and RCM, restrictive cardiomyopathy.
Figure 2
Figure 2. Frequency of clinical genetic cardiomyopathy panel testing by cardiomyopathy subtype.
DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; and RCM, restrictive cardiomyopathy.
Figure 3
Figure 3. Clinical genetic testing results in 81 cardiomyopathy patients by phenotype.
Results interpreted as pathogenic or likely pathogenic are considered positive. Patients who did not have cardiomyopathy panel testing were excluded. DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; RCM, restrictive cardiomyopathy; and VUS, variant of uncertain significance.
Figure 4
Figure 4. Frequency of positive exome testing results in children with cardiomyopathy by phenotype and family history status.
DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; and RCM, restrictive cardiomyopathy.
See this image and copyright information in PMC

References

    1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB; American Heart Association, Council on Clinical Cardiology Heart Failure, and Transplantation Committee, Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Group; Council on Epidemiology and Prevention . Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816. DOI: 10.1161/CIRCULATIONAHA.106.174287. - DOI - PubMed
    1. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58:2703–2738. DOI: 10.1016/j.jacc.2011.10.825. - DOI - PubMed
    1. Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail. 2018;24:281–302. DOI: 10.1016/j.cardfail.2018.03.004. - DOI - PMC - PubMed
    1. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8:1308–1339. DOI: 10.1016/j.hrthm.2011.05.020. - DOI - PubMed
    1. Miller EM, Wang Y, Ware SM. Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families. J Genet Couns. 2013;22:258–267. DOI: 10.1007/s10897-012-9544-4. - DOI - PubMed

Publication types

Associated data