Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that is characterized by left ventricular hypertrophy. Severity of HCM varies widely, from asymptomatic disease to patients with arrhythmias, heart failure, and in some instances sudden cardiac death (SCD). Because early diagnosis and treatment improves cardiac outcomes, genetic testing and counseling is a valuable resource for families affected by HCM.
Inheritance of HCM follows an autosomal dominant pattern, but can occur without a family history of HCM. Approximately 1 in 500 adults is affected by HCM and about 30% to 60% of patients with HCM have an identifiable disease-causing genetic variant.
This Guidelines Side-by-Side compares genetic testing recommendations for HCM from the National Society of Genetic Counselors (NSGC) and the American Heart Association (AHA) and American College of Cardiology (ACC) Joint Committee on Clinical Practice Guidelines that consists of AHA, ACC, American Medical Society for Sports Medicine (AMSSM), Heart Rhythm Society (HRS), Pediatric and Congenital Electrophysiology Society (PACES), and the Society for Cardiovascular Magnetic Resonance (SCMR).
Titles of Comparison
| Item | Genetic testing and counseling for hypertrophic cardiomyopathy: An evidence-based practice resource of the National Society of Genetic Counselors | 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines |
|---|---|---|
| Authoring Organization | National Society of Genetic Counselors | American Heart Association, American College of Cardiology, American Medical Society for Sports Medicine, Heart Rhythm Society, Pediatric and Congenital Electrophysiology Society, and Society for Cardiovascular Magnetic Resonance |
| Publication Date | November 2024 | June 2024 |
| Includes Graded Recommendations | No | Yes |
| Comments | Recommendations are based on the personal recommendations and experience of the authors | In addition to genetic testing for HCM there are recommendations for evaluation/testing and management of HCM |
| Guidelines | Full-Text Guideline Overview | Full-Text Guideline Summary Pocket Guide |
Key Takeaways
Both the NSGC and the AHA/ACC Joint Committee on Clinical Practice Guidelines agree on genetic testing and counseling for HCM. Some of the key recommendations include:
- Genetic testing and counseling should be performed by experts in genetics.
- Genetic testing should include the most common variants known to cause HCM.
- Some patients may also have testing done for syndromic forms of left ventricular hypertrophy (LVH).
- First degree relatives of patients with HCM should receive genetic testing.
- Cascade genetic testing for familial variants if helpful in determining which family members need serial cardiac screening.
- Because what is known about genetics is constantly changing, variants should be reviewed overtime for possible reclassification.
- Family planning is an important part of genetic counseling to help determine the risks of pregnancy and the risk of passing on HCM to potential offspring.
Recommendation Comparison
| Topic | NSGC | ACC/AHA/AMSSM/HRS/PACES/SCMR |
|---|---|---|
| Genetic Testing | Genetic testing should be offered to all individuals with a suspected or confirmed clinical diagnosis of HCM in the setting of appropriate genetic counseling. | In patients with HCM, genetic counseling by an expert in the genetics of cardiovascular disease is recommended so that risks, benefits, test results, and their clinical significance can be reviewed and discussed with the patient in a shared decision-making process. |
| - A three- to four-generation, cardiology-focused family history should be elicited as part of the genetic testing process. - In some situations, the most informative individual to test may be deceased and options for post-mortem genetic testing should be explored. | - In patients with HCM, evaluation of familial inheritance, including a 3-generation family history, is recommended as part of the initial assessment. - In families where a sudden unexplained death has occurred with a postmortem diagnosis of HCM, postmortem genetic testing is beneficial to facilitate cascade genetic testing and clinical screening in first-degree relatives. | |
| Selection of Genetic Test | Genetic tests should be selected, ordered, and interpreted in the setting of appropriate genetic counseling. - As a minimum, genetic testing should include genes with robust gene–disease association for non-syndromic HCM and inclusion of genes associated with syndromic forms of LVH may be valuable in some instances. | When performing genetic testing in a proband with HCM, the initial tier of genes tested should include genes with strong evidence to be disease-causing in HCM. - In patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause, a workup including genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy (“HCM phenocopies”) is recommended. |
| A cadence of variant review has not been formally established, though it is generally suggested that this should occur every 1–3 years. | In patients with HCM who have undergone genetic testing, serial reevaluation of the clinical significance of the variant(s) identified is recommended to assess for variant reclassification, which may impact diagnosis and cascade genetic testing in family members. | |
| Family Screening/ Cascade Testing | Family screening, including cardiac screening and cascade genetic testing, as appropriate, should be offered to at-risk relatives. Cascade genetic testing should be offered in the setting of appropriate genetic counseling without limitation of age. | In patients with HCM, genetic testing is beneficial to elucidate the genetic basis to facilitate the identification of family members at risk for developing HCM (cascade testing). |
| - Family screening is recommended for first-degree relatives of patients with HCM regardless of age and proband genotype. - Baseline cardiology testing is recommended for all first-degree, at-risk relatives and should include echocardiogram, electrocardiogram, and examination by a cardiologist. | In first-degree relatives of patients with HCM, both clinical screening (ECG and 2D echocardiogram) and cascade genetic testing (when a pathogenic/likely pathogenic variant has been identified in the proband) should be offered. | |
The key value of genetic testing for HCM arises from the opportunity to clarify genetic risk for relatives, as those that test negative for the familial variant may be released from serial cardiac screening and cannot pass HCM onto their biological children. | - For patients with HCM who have undergone genetic testing and were found to have no pathogenic variants (ie, harbor only benign or likely benign variants), cascade genetic testing of the family is not useful. - Ongoing clinical screening is not indicated in genotype-negative relatives in families with genotype-positive HCM, unless the disease-causing variant is downgraded to a variant of uncertain significance (VUS), likely benign, or benign variant during follow-up. | |
Pregnant individuals with HCM should receive specialized pregnancy care including discussion of current cardiac medications. Regarding risk for HCM in future biological children, expectant couples should be offered preconception genetic counseling. | In affected families with HCM, preconception and prenatal reproductive and genetic counseling should be offered. | |
| Cascade genetic testing of at-risk relatives for a VUS is not recommended as the presence or absence of the VUS does not provide informative or actionable information. | In patients with HCM who have a variant of uncertain significance (VUS), the usefulness of clinical genetic testing of phenotype-negative relatives for the purpose of variant reclassification is uncertain. | |
| Risk of SCD | Not Addressed | In adult patients with HCM, the usefulness of genetic testing in the assessment of risk of SCD is uncertain. |
Genetic Tests to Consider for HCM
| Test | NSGC | AHA/ACC/AMSSM/HRS/PACES/SCMR |
|---|---|---|
| Phenotype-Focused Gene Panel | - MYBPC3 - MYH7 - TNNT2 - TNNI3 - TPM1 - ACTC1 - MYL2 - TNNC1 Among all gene positive cases, MYBPC3 and MYH7 account for 83%, and TNNI3 and TNNT2 account for 9% of causal variants. | - MYBPC3 - MYH7 - TNNT2 - TNNI3 - TPM1 - ACTC1 - MYL2 - MYL3 |
| Other Genes Associated with HCM that may be Considered for Testing | - ACTN2 - ALPK3 - CACNA1C (Timothy Syndrome) - CSRP3 - DES (Desminopathy) - FHL1(Emery-Dreifuss Muscular Dystrophy) - FHOD3 - FLNC (Myofibrillar Myopathy) - GLA (Fabry Disease) - JPH2 - KLH24 - LAMP2 (Danon Disease) - MT-TI - PLN (Intrinsic Cardiomyopathy) - PRKAG2 (Cardiomyopathy) - PTPN11 (Noonan Syndrome) - RAF1 (Noonan Syndrome) - RIT1(Noonan Syndrome) - TRIM63 - TTR (Transthyretin Amyloidosis) | - PRKAG2 (glycogen storage disease) - LAMP2 (Danon disease) - 13 GLA (Fabry disease) - 34 transthyretin amyloid cardiomyopathy - Disease genes related to RASopathies |
This concludes our Guidelines Side-by-Side on genetic testing for hypertrophic cardiomyopathy. Don’t forget to sign up for alerts to stay informed on the latest published guidelines and articles.
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