From the Guidelines
Genetic testing for Hypertrophic Obstructive Cardiomyopathy (HOCM) primarily involves comprehensive gene panel testing that examines multiple sarcomere protein genes simultaneously, focusing on the 8 core sarcomere genes most frequently implicated in HOCM, including MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1, as recommended by the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline 1. The most common test is a cardiomyopathy gene panel that analyzes 50-100 genes associated with various forms of cardiomyopathy. Next-generation sequencing (NGS) technology is typically used for these panels, allowing for rapid and cost-effective analysis of multiple genes. For families with known HOCM mutations, targeted genetic testing can be performed to identify specific variants already identified in other family members. Whole exome sequencing may be used in complex cases where standard panels don't yield results. Genetic testing is particularly valuable for family screening, allowing identification of at-risk relatives before symptoms develop, enabling early monitoring and intervention. Testing should be accompanied by genetic counseling to help patients understand the implications of results, including the possibility of variants of uncertain significance that may be difficult to interpret clinically, as highlighted in the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline 1. Some key points to consider when interpreting genetic testing results include:
- The usefulness of genetic testing in the assessment of risk of SCD is uncertain, as noted in the 2020 AHA/ACC guideline 1.
- In patients with HCM who harbor a variant of uncertain significance, the usefulness of clinical genetic testing of phenotype-negative relatives for the purpose of variant reclassification is uncertain, as mentioned in the 2020 AHA/ACC guideline 1.
- For patients with HCM who have undergone genetic testing and were found to have no pathogenic variants, cascade genetic testing of the family is not useful, as stated in the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline 1. Key genes associated with HOCM include:
- MYH7
- MYBPC3
- TNNI3
- TNNT2
- TPM1
- MYL2
- MYL3
- ACTC1, as identified in the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline 1. Genetic counseling is essential to ensure that patients understand the implications of their genetic test results and to guide clinical decision-making, as emphasized in the 2020 AHA/ACC guideline 1.
From the Research
Genetics Tests for Diagnosing HOCM
The following genetics tests are available to diagnose Hypertrophic Obstructive Cardiomyopathy (HOCM):
- Mutation screening of genes implicated in HCM, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 2
- Semiautomated MALDI-TOF mass spectrometry using the Sequenom MassArray System and iPLEX Gold genotyping chemistry to detect known mutations 3
- Direct sequencing of the coding exons and flanking intronic regions of HCM genes, including MYBPC3, MYH7, TNNT2, TNNI3, and TPM1 3
- Gene panel testing, which includes a range of genes associated with HCM, although the validity of some of these genes is still being evaluated 4
Genes Associated with HOCM
The following genes have been associated with HOCM:
- MYBPC3: a frequent cause of HCM, with a novel mutation (G13999T) identified in a patient with HOCM 3
- MYH7: a gene commonly mutated in HCM patients, with somatic mutations not representing an important etiologic pathway in HCM 2
- TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3: genes with definitive evidence of disease causation in HCM 4
- CSRP3, TNNC1, and JPH2: genes with moderate evidence of disease association in HCM 4
Clinical Validity of Genetics Tests
The clinical validity of genetics tests for HOCM is crucial to ensure accurate diagnosis and treatment. A systematic approach to evaluating gene-disease associations is necessary to categorize genes as having definitive, strong, moderate, limited, or no evidence of disease causation 4