The following are key points to remember from a European Society of Cardiology (ESC) clinical consensus statement on integration of genetic testing into diagnostic pathways for cardiomyopathies:

1. As outlined in a previous ESC Council on Cardiovascular Genomics position statement, collecting a detailed family history and pertinent clinical data for patients with cardiomyopathies is needed to guide potential use of genetic testing.
2. Cardiologists caring for patients with cardiomyopathies should be able to communicate why a potential genetic etiology is being considered and discuss the indications, family implications, and clinical impact of genetic testing. This can be done in collaboration with trained professionals (e.g., geneticists, genetic counselors).
3. Cardiologists have various roles in the genetic testing process, which include clinical phenotyping of patients and relatives, deciding if genetic testing is appropriate and what specific testing is required, interpreting results, communicating findings with the patient, and creating patient management and family screening plans.
4. Multigene panel genetic testing is generally the first-line approach, which allows for testing of phenotypically similar cardiomyopathies. Single-gene, whole-exome, and whole-genome sequencing are also available, with specific use determined by clinical features, pretest probability, cost, and desire for comprehensive testing.
5. Genotype-phenotype discordance may occur when the genetic variants associated with disease do not align with the clinical phenotype of the patient. In these situations, additional family screening and prospective family monitoring are helpful. In general, the clinical phenotype should guide clinical decision-making.
6. A standardized framework for interpreting gene variants exists (pathogenic, likely pathogenic, variants of uncertain significance, likely benign, benign). Bioinformatics tools also exist for variant interpretation without the use of patient-specific clinical data, which can lead to different genetic testing interpretation.
7. Variants of unknown significance (VUS) are rare or unique genetic variants that do not meet criteria to be classified as pathogenic or benign. Further investigation may be needed (e.g., functional assessment) to refine the interpretation of these results. The classification of a VUS may change over time as new data are available.
8. Functional assessments can be useful when the interpretation of a VUS has implications on clinical management and DNA-based testing is inconclusive. RNA-based functional testing can assess pathogenicity of a VUS by examining the effects on splicing and expression. Protein-based functional testing can assess pathogenicity of a VUS by examining expression of mutated and nonmutated proteins.
9. This statement advocates for cardiologists having a deeper understanding of the genetic testing process to maximize use of this valuable diagnostic pathway.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Genetic Testing, Cardiomyopathies

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