3 research outputs found
Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study
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
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Outcome Predictors for Pediatric Dilated Cardiomyopathy: A Systematic Review
Dilated cardiomyopathy comprises the largest group of pediatric cardiomyopathy functional types and is the most common indication for heart transplant in children over 5 years old. Prognostic factors for this condition have long been sought by many researchers. In a systematic review of these factors, we found 32 relevant articles published since 1976. Four studies report finding no predictive factors. In the remaining 28 studies, several factors indicating better prognosis stand out across multiple articles: younger age at diagnosis, higher left-ventricular fractional shortening and ejection fraction, and the presence of myocarditis. Results for other factors conflict across studies: severe mitral regurgitation, arrhythmias, and a family history of cardiomyopathy. Elevated left-ventricular end diastolic pressure was statistically significant in two studies, but it may be of limited utility as a result of its invasiveness. Although most children have congestive heart failure at presentation, only two studies found it to be a significant predictor of mortality. The largest study of this factor qualified the increased risk to 1 year after presentation. Other significant predictors that have not been analyzed or reported by more than one study group, are right ventricular failure and impaired cardiac adrenergic innervation, as detected by radiolabeled meta-iodobenzylguanidine imaging. Although 1- and 5-year survival rates have steadily improved, as more children with DCM receive cardiac transplants, event-free survival rates (the absence of "heart death" resulting in death or transplant) are similar to those from decades ago. A unified risk algorithm may assist in clinical decision-making but requires more studies. Other studies are needed to assess the post-transplant survival experience
The genetic architecture of pediatric cardiomyopathy
To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10−16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
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