Evaluation of Genetic Causes of Cardiomyopathy in Childhood

Cardiomyopathy frequently has a genetic basis. In adults, mutations in genes encoding components of the sarcomere, cytoskeleton, or desmosome are frequent genetic causes of cardiomyopathy. Although children share these causes, ~30% of children have an underlying metabolic, syndromic, or neuromuscular condition causing their cardiomyopathy, making the aetiologies more diverse in children as compared with adults. Although some children present with obvious signs or symptoms of metabolic, syndromic, or neuromuscular disease, other cases may be quite subtle, requiring a high level of suspicion in order to diagnose them. In general, the younger the child, the more extensive the differential. Advantages of identifying the underlying genetic cause of cardiomyopathy in the paediatric population include confirming the diagnosis in ambiguous cases, facilitating appropriate surveillance and management of cardiac and extra-cardiac diseases, providing prognostic information, and establishing the genetic basis in the family, thereby allowing the identification of at-risk relatives and institution of appropriate family screening as indicated. For these reasons, genetic testing is increasingly recognised as standard of care, and guidelines for genetic counselling, testing, and incorporation of family-based risk assessment have been established. Therapies aimed at treating specific genetic aetiologies of cardiomyopathy are emerging and are exciting new developments that require increasingly sophisticated approaches to diagnosis. As genetic testing capabilities continue to expand technically, careful interpretation, knowledgeable clinical utilisation, and appropriate dissemination of genetic information are important and challenging components of clinical care

Genetics of paediatric cardiomyopathies

PURPOSE OF REVIEW: Paediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the paediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. RECENT FINDINGS: With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified at a rapid rate. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences in pathogenesis from adult cardiomyopathy. Therapy targeted towards the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. SUMMARY: Genetics is moving at a rapid pace in paediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. Although interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted towards the underlying genetic cause is beginning to be realized

Genetic and Developmental Basis of Cardiovascular Malformations

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1% to 5% of all live births. Genetic, epigenetic, and environmental factors all influence the development of CVMs, and an improved understanding of the causation of CVMs is a prerequisite for prevention. Cardiac development is a complex, multistep process of morphogenesis that is under genetic regulation. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are still identified infrequently. This article discusses the key genetic concepts characterizing human CVMs, their developmental basis, and the critical developmental and genetic concepts underlying their pathogenesis

Toward Personalized Medicine: Does Genetic Diagnosis of Pediatric Cardiomyopathy Influence Patient Management?

A goal of personalized medicine is to provide increasingly sophisticated, individualized approaches to management and therapy for disease. Genetics is the engine that drives personalized medicine, holding the promise of therapeutics directed toward the unique needs of each patient. The 3(rd) International Conference on Cardiomyopathy in Children provided a forum to discuss the current status of personalized approaches to diagnosis, management, and therapy in the pediatric cardiomyopathy population. This review will focus on the importance of genetic diagnosis in this population as a necessary first step toward understanding the best approach to management and influencing disease outcome. The genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the ability to risk stratify based on genotype, and the impact on cascade screening in family members will be discussed

Genetics and Genetic Testing in Congenital Heart Disease

Congenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extra-cardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD etiologies. These distinctions remain clinically relevant, particularly with regard to management; however, identification of genetic causes in patients with presumably non-syndromic CHD indicates that isolated CHD can also be genetic in origin. In recent years, the field of cardiac genetics has benefited from a growing understanding of the complex molecular mechanisms underpinning heart development, and the extreme genetic heterogeneity of CHD is increasingly appreciated. Progress has been largely supported by improvements in genetic testing technology derived from worldwide efforts to accurately and economically characterize the full breadth of human genomic variation. The last fifteen years in particular have witnessed emergence and refinement of novel cytogenetic and sequencing technologies, which have proven to be enormously effective tools for both diagnosis and identification of novel CHD-causing genes. These advancements have led to an increasing need for cardiac care providers to be well versed in the molecular genetic origins of CHD and to have working knowledge of the benefits and limitations of available testing methods. In this review, we provide a general overview of key morphologic, molecular, and signaling mechanisms relevant to heart development before summarizing overall progress in the molecular genetic analyses of CHDs and current recommendations for clinical application of genetic testing. Particular emphasis is placed on the utility and limitations of chromosomal microarray analyses (CMAs) and on emerging clinical roles for whole exome sequencing (WES) and other next-generation sequencing (NGS) technologies

The Current Landscape of Genetic Testing in Cardiovascular Malformations: Opportunities and Challenges

Human cardiovascular malformations (CVMs) frequently have a genetic contribution. Through the application of novel technologies, such as next-generation sequencing, DNA sequence variants associated with CVMs are being identified at a rapid pace. While clinicians are now able to offer testing with NGS gene panels or whole exome sequencing to any patient with a CVM, the interpretation of genetic variation remains problematic. Variable phenotypic expression, reduced penetrance, inconsistent phenotyping methods, and the lack of high-throughput functional testing of variants contribute to these challenges. This article elaborates critical issues that impact the decision to broadly implement clinical molecular genetic testing in CVMs. Major benefits of testing include establishing a genetic diagnosis, facilitating cost-effective screening of family members who may have subclinical disease, predicting recurrence risk in offsprings, enabling early diagnosis and anticipatory management of CV and non-CV disease phenotypes, predicting long-term outcomes, and facilitating the development of novel therapies aimed at disease improvement or prevention. Limitations include financial cost, psychosocial cost, and ambiguity of interpretation of results. Multiplex families and patients with syndromic features are two groups where disease causation could potentially be firmly established. However, these account for the minority of the overall CVM population, and there is increasing recognition that genotypes previously associated with syndromes also exist in patients who lack non-CV findings. In all circumstances, ongoing dialog between cardiologists and clinical geneticists will be needed to accurately interpret genetic testing and improve these patients' health. This may be most effectively implemented by the creation and support of CV genetics services at centers committed to pursuing testing for patients

Genetic causes of cardiomyopathy in children: First results from the Pediatric Cardiomyopathy Genes Study

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