Version May 2024
INTRODUCTION — This monograph discusses interpretation of genetic testing that includes genetic loci associated with familial hypertrophic cardiomyopathy (HCM).
It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the clinical care of the tested individual. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)
HOW TO READ THE REPORT — Confirm the report belongs to the patient and the interpretation is current. An approach is summarized in a checklist (table 1). A glossary of terms related to genetic testing is also provided (table 2).
Genetic test reports indicate the gene variant(s) identified and provide the laboratory's interpretation of pathogenicity at the time. Variants (mutations) are classified in five categories of pathogenicity (table 3). Pathogenicity classification, especially for variants of uncertain significance (VUS), may be revised over time as new evidence emerges [2]. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
Genetic testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. If the initial results would impact clinical care and were obtained from direct-to-consumer testing or a research study, repeat the test in a CLIA-certified laboratory to assure proper specimen collection, labeling, and reporting.
DISEASE ASSOCIATION — HCM is a heart muscle disease most often caused by variants in one of the genes that encodes a component of the sarcomere contractile apparatus. HCM is autosomal dominant with variable expressivity and age-related penetrance.
HCM phenotype — HCM is diagnosed by the presence of left ventricular hypertrophy (LVH, ≥15 mm thickening anywhere in the LV wall) in the absence of another identifiable cause (hypertension or valve disease). LVH onset is typically in puberty. The clinical course is relatively benign for most patients, although symptoms related to heart failure or arrhythmia may occur, including chest pain, dyspnea and, in a small subgroup, sudden cardiac death. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)
Diagnostic evaluation involves electrocardiogram (ECG) and echocardiogram. The ECG is abnormal in 90 percent of individuals with HCM, though no specific pattern is diagnostic. Cardiac magnetic resonance imaging (MRI) should be considered if the echocardiogram is of nondiagnostic quality, if LV wall thickness is borderline abnormal, or if the ECG is abnormal and the echocardiogram is normal or ambiguous.
HCM genes — A pathogenic or likely pathogenic variant in one of eight genes encoding sarcomeric proteins is identified in close to 50 percent of patients with HCM; three additional genes show moderate evidence of causation (table 4) [3]. Among successfully genotyped patients with HCM, mutations affecting MYBPC3 and MYH7 account for up to 70 percent of the variants, and rarer variants for the remainder [4]. (See 'MYBPC3' below and 'MYH7' below.)
Mutations cannot be used to predict the clinical presentation or course of HCM in an individual patient. Although there are trends of genotype-phenotype associations, the relationship is neither consistent nor definitive enough to predict outcomes, hemodynamics (eg, obstruction versus non-obstruction), or the pattern or magnitude of LVH in an individual patient. Morphologic expression and clinical course can differ among relatives with the same disease-causing sarcomeric mutation.
MYBPC3 — Pathogenic variants affecting the gene for cardiac myosin-binding protein C (MYBPC3) are most common, seen in up to 30 percent of patients with HCM. Phenotypic expression is heterogeneous; approximately 40 percent of adults under the age of 50 with an MYBPC3 mutation do not have cardiac hypertrophy [5].
MYH7 — There are >50 reported pathogenic variants in the gene for cardiac myosin heavy chain 7 beta subunit (MYH7), found in up to 25 percent of patients with HCM. While there is substantial heterogeneity in phenotypic expression, in general these variants are associated with a higher penetrance of disease, younger age at diagnosis, and more severe hypertrophy than mutations in MYBPC3 [6].
TNNT2 — Pathogenic variants in the gene for cardiac troponin T (TNNT2) are responsible for 4 to 15 percent of HCM; they are generally associated with less hypertrophy than mutations affecting myosin. Some individuals will have normal cardiac wall thickness but may still have myocyte disarray.
TNNI3 — Pathogenic variants in the gene for cardiac troponin I (TNNI3), identified in 2 to 7 percent of HCM cases, have a disease penetrance of approximately 50 percent and may be associated with dilated or restrictive physiology [7,8]. Disease expression within families may be extremely variable [9].
Rarer variants — Pathogenic variants in the genes for tropomyosin 1 (TPM1), cardiac myosin regulatory light chain 2 (MYL2), myosin essential light chain 3 (MYL3), and alpha-cardiac actin (ACTC1) are each associated with <5 percent of cases of HCM. Penetrance cannot be estimated given the limited data.
INDIVIDUALS WITHOUT KNOWN HCM
Pathogenic or likely pathogenic variant — Referral for cardiology evaluation and genetic counseling is appropriate when a pathogenic or likely pathogenic variant is identified, regardless of family history of HCM (algorithm 1). Clinical evaluation should include an electrocardiogram (ECG) and echocardiogram. Cardiac magnetic resonance imaging (MRI) may be considered if the echocardiogram is of nondiagnostic quality, if left ventricular (LV) wall thickness is borderline abnormal, or if the ECG is abnormal and the echocardiogram is normal or nondiagnostic. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Diagnostic evaluation'.)
Genotype and phenotype positive — Patients found to have LV hypertrophy (LVH) on cardiac imaging without other explanation should be counseled regarding HCM disease management, including activity restrictions. Results of genetic testing do not impact individual HCM patient management strategies. Decisions regarding indications for intervention, such as an implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death (SCD), are based upon the risk profile of the individual patient (including age, structural and hemodynamic features, findings on ambulatory ECG, history of syncope, or SCD in a first-degree relative). (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death" and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Recommendations for ICD therapy'.)
Patients with HCM and a pathogenic or likely pathogenic variant should be advised to inform their first-degree relatives to seek consultation regarding clinical evaluation for HCM and/or testing for the variant identified in the proband. (See 'Evaluation of first degree relatives' below.)
Genotype positive, phenotype negative — Patients without LVH on imaging who have a pathogenic or likely pathogenic variant are genotype positive, phenotype negative (G+ P-). Approximately 50 percent of G+ P- individuals will have an abnormal ECG. The likelihood of phenotypic conversion (development of LVH) has been estimated at rates of <1 to 5 percent annually. However, an increasing number of G+ P- individuals are identified by genetic testing in mid to older age, indicating that many G+ P- family members remain gene carriers throughout life without developing disease.
When the echocardiogram is normal in a patient with a pathogenic or likely pathogenic variant in an HCM gene, particularly if the ECG suggests LVH, an MRI may be helpful to identify focal areas of limited LVH, consistent with a clinical diagnosis of HCM.
There is no compelling evidence to suggest that G+ P- individuals are at increased risk for sudden death, and United States consensus recommendations do not exclude such individuals from participation in recreational or competitive sports. However, HCM surveillance is recommended and should include an initial ECG and echocardiography, with echocardiography repeated every one to two years through puberty and every three to five years at least through age 40 to 50 years.
G+ P- individuals should be advised to inform their at-risk family members to seek genetic consultation regarding testing for the identified variant. (See 'Evaluation of first degree relatives' below.)
Variant of uncertain significance — Whether further evaluation is indicated for asymptomatic individuals found to have a variant of uncertain significance (VUS) is best determined by shared decision-making with a genetics expert.
Variant reclassification — As new evidence emerges over time, a variant may be reclassified to a pathogenic variant, VUS, or benign variant. Each patient's genetic test results should be reevaluated every few years to determine if there has been a reclassification. This can be done by checking a database such as ClinVar, contacting the laboratory that performed the initial test, or consulting a specialist (clinical geneticist, genetic counselor, or individual with expertise in the specific genetic disorder) [10]. (See 'Locating a genetics expert' below.)
INDIVIDUALS WITH KNOWN HCM — Patients with HCM should be referred to a cardiologist for counseling and management. The diagnosis of HCM is based on clinical criteria and is not ruled out if genetic testing does not identify a variant associated with HCM. Such patients may have variants that were not included in the gene panel, were not detected, or were not classified as a pathogenic gene variant or variant of uncertain significance (VUS). Management is discussed separately. (See 'UpToDate topics' below.)
Genetic testing in an individual with a clinical diagnosis of HCM is most valuable to identify a risk variant for cascade (predictive) testing of at-risk relatives. Patients with HCM should be advised to inform relatives to seek consultation for clinical testing and genetic counseling. (See 'Evaluation of first degree relatives' below.)
EVALUATION OF FIRST DEGREE RELATIVES — Since HCM is autosomal dominant, first-degree relatives have a 50 percent chance of carrying the abnormal gene. We suggest that first-degree relatives of patients with HCM undergo clinical evaluation with electrocardiogram (ECG) and echocardiogram, with subsequent genetic testing if HCM is not clinically diagnosed. However, some experts recommend genetic testing as the initial evaluation when a mutation has been identified in the proband.
If a pathogenic or likely pathogenic variant is identified in the affected individual, relatives who test negative for the identified variant can be reassured that they are unlikely to develop HCM. Relatives who test positive for the identified variant (when clinical testing does not indicate left ventricular hypertrophy [LVH]) are considered genotype positive, phenotype negative (G+ P-). (See 'Genotype positive, phenotype negative' above.)
If gene testing in the proband fails to identify a pathogenic or likely pathogenic variant, genetic testing in relatives will not help determine if they are at risk of developing HCM. For the relatives of a proband with a negative genetic screen, screening of children and adolescents with cardiac imaging may be appropriate at any time after the HCM diagnosis is made in the proband. This evaluation should begin no later than onset of puberty; any child with symptoms suggestive of HCM should be evaluated regardless of when their symptoms manifest [11]. The value of earlier routine screening with echocardiography in preadolescent relatives remains unresolved. Adult relatives should also be screened with imaging at the time HCM diagnosis is determined in the proband.
If clinical suspicion for HCM remains for the proband or relatives, we reevaluate the proband's genetic test result to assess for possible reclassification to a pathogenic variant or VUS. (See 'Variant reclassification' above.)
RESOURCES
UpToDate topics
●Diagnosis of HCM:
•Genetic testing – (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)
•Diagnosis and prognosis – (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy: Natural history and prognosis".)
●Management of HCM:
•Medical therapy for heart failure – (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction".)
•Treatment of left ventricular outflow tract obstruction – (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)
•Management of ventricular arrhythmias and sudden cardiac death risk – (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".)
●Genetics concepts:
•Pathogenicity – (See "Secondary findings from genetic testing".)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Locating a genetics expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
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