There is 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 designed to estimate 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 attention [11
Benefits of genetic testing include establishing a causal diagnosis, providing definitive identification of at risk family members, and providing cost-effective screening and surveillance. Particularly in the pediatric setting, where cardiomyopathy is so heterogeneous, the benefit of establishing a causal diagnosis should not be underestimated. It is, in fact, critical for early and proper management of extra-cardiac symptoms for syndromic, metabolic, or neuromuscular cases.
In order to use genetic testing most effectively, it is important to understand its limitations in addition to the benefits. Limitations will be discussed in more detail below, and include the facts that 1) genotype-phenotype correlations are still emerging 2) testing does not always yield unambiguous results and 3) some causative genes remain unidentified. Each of these limitations represents a unique area for future research.
Currently, there are insufficient data regarding the prognostic information provided by specific genotypes. After initial (over)enthusiasm about genotype-phenotype correlations and the ability to risk stratify based on mutation type, testing larger cohorts has demonstrated a more complex reality. This was, in fact, a predicted outcome of more globally applied genetic testing and should not be viewed as a cause for negativity regarding the importance of identifying the molecular etiology. Research-based identification of causative genes has historically relied on an ascertainment bias in which the most severely affected individuals, with highly penetrant mutations, are the first identified. Thus, for the majority of genetic disease, discovery of the genetic basis and description of the phenotype is followed by an expansion of the phenotypic spectrum and modification and re-interpretation of initial molecular results. Genetic testing provides important benefits to clinical care as described above. However, clinical research is required to determine the full implication of genetic results in aggregate. Re-classification of mutations with incorporation of clinical information, refinement of genotype-phenotype predictions, and identification of susceptibility alleles or modifier genes are all research needs that can only be addressed with information derived from large cohorts. There are important opportunities for further development of our understanding of the genetic basis of pediatric cardiomyopathy and the development of algorithms for clinical management.
Genetic testing in the cardiomyopathy population, particularly in HCM, results in some of the highest diagnostic yields of any type of genetic test. Nevertheless, negative and indeterminate tests (variants of uncertain significance) are inevitable and are intrinsic to the limitations of our current technical and clinical knowledge base. Interpretation of genetic testing is strengthened by evaluating results in large populations derived from clinical genetic testing programs that avoid the biases that occur when a small number of subjects are studied in a research setting. There are specific criteria for determining the pathogenicity of a variant, but novel rare variants pose problems for interpretation. Ultimately, each commercial laboratory decides the final interpretation based on the published literature, bioinformatic prediction programs, clinical information, and their internal testing and reporting practices. An understanding of the possible outcomes of the test, and how each possible outcome will be utilized clinically, is important for both the care provider and the patient. Future research also is needed in development of strategies to assess functional consequences of rare variants.
Finally, it is clear that we haven’t yet identified all genetic causes of cardiomyopathy. Diagnostic yield varies depending on the type of cardiomyopathy. Patients should be counseled carefully about the interpretation of negative testing and its implications with regard to at risk family members. In addition to identification of novel causative genes, future research will also be directed at delineating the importance of regulatory regions, enhancers, microRNA, and copy number variation in the development of disease. Recent technical developments have led to a number of general discoveries about genetic disease and genomic architecture, but these have not yet been applied in a rigorous way to the field of pediatric cardiomyopathy. Studies directed toward understanding complex inheritance patterns and gene x environment interactions will provide additional information about disease susceptibility.