Perspective:

This is an update on genetic testing in patients with confirmed or suspected hypertrophic cardiomyopathy and their family. The following are 10 points to remember:

1. Hypertrophic cardiomyopathy (HCM) is a familial cardiac disease with a prevalence of 1:500. HCM has a heterogeneous phenotypic expression that is inherited most commonly in an autosomal dominant pattern with variable penetrance.

2. There have been >11 causative genes identified in HCM containing >1,400 mutations. Genes typically encode proteins of the thick and thin myofilaments of the sarcomere or Z discs. Over 70% of HCM patients with positive gene tests have mutations in MYH7 (B-myosin heavy gene) or MBPC3 (myosin binding protein C).

3. Mutations identified on gene testing can be considered likely pathogenic, nonpathogenic, or a variant of uncertain significance (VUS). Mutations can move from one category to another as scientific data evolve. Testing results regarding the molecular diagnosis and ascription of identified mutations to “pathogenic status” is given to ordering clinicians in “probabilities”—not as a “yes/no” result. Patients may have unknown mutations or mutations in genes that remain of uncertain significance (VUS).

4. Genetic testing can assist in ambiguous diagnoses of cardiac hypertrophy such as HCM, hypertension-induced heart failure, or “athletes” heart. However, yields from genetic testing are low (only ~50% of HCM patients test positive), and a negative test is inconclusive.

5. Screening family members of patients with known HCM should start with clinical testing (electrocardiogram and echocardiogram) to identify phenotype-positive relatives. Genetic testing may be useful for those family members without an HCM phenotype. However, the HCM patient (proband) must have an identifiable gene for family testing to be of use. Given the low yield of genetic testing in HCM probands, a minority of families overall will benefit from family genetic screening.

6. False-negative testing (negative genetic test but +HCM disease) in family members can arise from de-novo family member mutations or inheritance of an unknown HCM gene mutation (proband heterozygous for two HCM gene mutations and offspring inherits unknown mutation only). False-positive testing can occur if a pathogenic mutation is later reassigned to VUS.

7. Family members who are genotype positive, but phenotype negative (e.g., no left ventricular hypertrophy on echocardiogram) should have extended HCM surveillance with imaging through midlife. At present, guidelines do not exclude them from sports.

8. Mutations do not prognosticate HCM severity (i.e., benign vs. malignant clinical course).

9. Patients and family members who undergo genetic testing should receive pre- and post-test counseling. The Genetic Information Non-Discrimination Act (GINA) prevents employers and health insurance providers from denying or terminating insurance or employment due to genetic testing results. However, this rule does not apply to military personnel or to life, disability, and long-term care insurance.

10. The authors argue that a standardized approach to mutation interpretation is needed to achieve confidence in, and greater utility for, genetic testing in the clinical community.