Genetic diagnosis in pediatric cardiomyopathy: Clinical application and research perspectives☆

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Abstract

There has been tremendous growth in the application of genetics to the clinical practice of pediatric cardiomyopathy. The identification of the genetic basis for cardiomyopathies is important for establishing a causal diagnosis, providing definitive identification of at risk family members, and providing cost-effective screening and surveillance. Additional research is needed to better understand the genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the best approach to cardiac surveillance and genetic testing, and the utility of genotyping for individual risk stratification. As the technology for evaluation of the human genome continues to improve, there is an increasing need for assessment of clinical relevance and utility. This is coupled with an ongoing need for education and training of professionals to interpret and implement genomics in a clinical setting.

Introduction

The Second International Conference on Cardiomyopathy in Children provided a forum for clinicians and scientists to discuss the current status of clinical care and research relevant to pediatric cardiomyopathy and identify critical questions and areas requiring additional research. There has been tremendous growth in the application of genetics to pediatric cardiomyopathy since the initial conference in 2006. The expanded availability of clinical molecular genetic testing for cardiomyopathy has significantly changed the landscape for clinical evaluation. Additional research is needed to better understand the genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the best approach to cardiac surveillance and genetic testing, and the utility of genotyping for individual risk stratification and, ultimately, more personalized therapy. This report summarizes the current status of genetic testing for pediatric cardiomyopathy and highlights some focus areas for future investigation.

Section snippets

The genetic basis of pediatric cardiomyopathy

Cardiomyopathies with known genetic causes can be broadly classified by pathophysiology into 5 types: hypertrophic (HCM), dilated (DCM), restrictive (RCM), left ventricular noncompaction (LVNC), and arrhythmogenic right ventricular cardiomyopathy (ARVC). The latter is infrequently identified in children. HCM, DCM, RCM, and LVNC all occur in childhood with a bimodal age distribution. One peak occurs in infancy (less than 1 year of age) and is characterized by the worst outcomes and broadest

Recommendations for clinical genetic evaluation and testing

A Heart Failure Society of America Practice Guideline was published by Hershberger et al. in 2009 to provide evidence based guidelines for cardiac surveillance and genetic testing in patients with possible familial or genetic causes of cardiomyopathy [11]. The guidelines address the level of evidence for clinical validity and clinical utility in making recommendations. Key components of the genetic recommendations include: 1) generate a 3 generation pedigree for all patients with cardiomyopathy

Availability of genetic testing

Clinical genetic testing should be performed in a laboratory that is accredited by Clinical Laboratory Improvement Amendment (CLIA) standards. Genetic testing for cardiomyopathy is changing rapidly and comprehensive molecular panels are currently available. Because of the heterogeneity of causes in pediatric cardiomyopathy, it is difficult to create an algorithm for genetic testing that is widely applicable, since testing should be guided by the differential for a specific patient. Clinical

The utility of genetic testing

There is a reason for optimism that genetic testing will improve the care of patients with cardiomyopathy [12]. Because testing has been clinically available for a relatively short time period, there are no published studies to compare outcomes in individuals that received testing versus those that did not. Furthermore, studies to examine the benefit to at risk family members are difficult to design and implement. The utility of genetic testing is an important topic that has received recent

Genomics and medicine

Isolated cardiomyopathy is most frequently the result of point mutations or small insertions or deletions in genes encoding sarcomeric or cytoskeletal proteins. Although recurrent mutations have been identified in multiple families, many disease causing mutations are private, occurring in a single family. This lack of a mutational “hot spot”, combined with the marked locus heterogeneity in cardiomyopathy, makes genetic testing challenging. Using traditional Sanger sequencing, there is

Conclusions

An understanding of the genetic basis of cardiomyopathy has come a long way from the initial description of MYH7 mutations in HCM. Genetic testing has transitioned from a research-only tool to an important component of the diagnostic evaluation of patients with cardiomyopathy and extension of care to at risk family members. The incorporation of genetic testing into clinical care is cost effective and allows for earlier detection and improved prevention of adverse events. Pediatric

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Supported by the Children's Cardiomyopathy Foundation, Cincinnati Children's Hospital Translational Research Institute and NIH (HL087000-01A1). There are no relationships with industry.

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