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

Stephanie M Ware, James D Wilkinson, Muhammad Tariq, Jeffrey A Schubert, Arthi Sridhar, Steven D Colan, Ling Shi, Charles E Canter, Daphne T Hsu, Steven A Webber, Debra A Dodd, Melanie D Everitt, Paul F Kantor, Linda J Addonizio, John L Jefferies, Joseph W Rossano, Elfriede Pahl, Paolo Rusconi, Wendy K Chung, Teresa Lee, Jeffrey A Towbin, Ashwin K Lal, Surbhi Bhatnagar, Bruce Aronow, Phillip J Dexheimer, Lisa J Martin, Erin M Miller, Lynn A Sleeper, Hiedy Razoky, Jason Czachor, Steven E Lipshultz, Pediatric Cardiomyopathy Registry Study Group, Stephanie M Ware, James D Wilkinson, Muhammad Tariq, Jeffrey A Schubert, Arthi Sridhar, Steven D Colan, Ling Shi, Charles E Canter, Daphne T Hsu, Steven A Webber, Debra A Dodd, Melanie D Everitt, Paul F Kantor, Linda J Addonizio, John L Jefferies, Joseph W Rossano, Elfriede Pahl, Paolo Rusconi, Wendy K Chung, Teresa Lee, Jeffrey A Towbin, Ashwin K Lal, Surbhi Bhatnagar, Bruce Aronow, Phillip J Dexheimer, Lisa J Martin, Erin M Miller, Lynn A Sleeper, Hiedy Razoky, Jason Czachor, Steven E Lipshultz, Pediatric Cardiomyopathy Registry Study Group

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.

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. Characteristics of 152 children in…
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. Frequency of clinical genetic cardiomyopathy…
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. Clinical genetic testing results in…
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. Frequency of positive exome testing…
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.

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