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


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.

SUBMITTER: Ware SM 

PROVIDER: S-EPMC8200745 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Ware Stephanie M SM   Wilkinson James D JD   Tariq Muhammad M   Schubert Jeffrey A JA   Sridhar Arthi A   Colan Steven D SD   Shi Ling L   Canter Charles E CE   Hsu Daphne T DT   Webber Steven A SA   Dodd Debra A DA   Everitt Melanie D MD   Kantor Paul F PF   Addonizio Linda J LJ   Jefferies John L JL   Rossano Joseph W JW   Pahl Elfriede E   Rusconi Paolo P   Chung Wendy K WK   Lee Teresa T   Towbin Jeffrey A JA   Lal Ashwin K AK   Bhatnagar Surbhi S   Aronow Bruce B   Dexheimer Phillip J PJ   Martin Lisa J LJ   Miller Erin M EM   Sleeper Lynn A LA   Razoky Hiedy H   Czachor Jason J   Lipshultz Steven E SE  

Journal of the American Heart Association 20210428 9


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 Res  ...[more]

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