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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Martin S Maron, MD
- Section Editor:
- William J McKenna, MD
- Deputy Editors:
- Jennifer S Tirnauer, MD
- Susan B Yeon, MD, JD, FACC
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 in the clinical care of the individual who was tested. These subjects are discussed separately in UpToDate . (See 'UpToDate topics' below.)
HOW TO READ THE REPORT — Confirm that the report belongs to the patient and that the interpretation is current. An approach to reviewing a genetic test report is summarized in a checklist (table 1). A glossary of terms related to genetic testing is also provided (table 2).
Reports of genetic testing indicate the gene variant(s) identified and provide the laboratory's interpretation of pathogenicity at the time of the report. Variants (mutations) are classified in five categories of pathogenicity (table 3). Pathogenicity classification, especially for variants of uncertain significance (VUSs), may be revised over time as new evidence emerges . (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 with established procedures to assure proper specimen collection, labeling, and reporting.
DISEASE ASSOCIATION — HCM is a heart muscle disease most often caused by mutations in one of several genes that encode components of the sarcomere contractile apparatus. HCM is inherited in an autosomal dominant Mendelian pattern with variable expressivity and age-related penetrance.
HCM phenotype — HCM is diagnosed by the presence of left ventricular (LV) hypertrophy (LVH, ≥15 mm thickening anywhere in the LV wall) in the absence of any other identifiable cause (eg, hypertension or valve disease). The onset of LVH is typically in puberty. The clinical course of HCM is relatively benign for most patients, although a variety of 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 for HCM involves an 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) . 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 . (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 — Mutations 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 .
MYH7 — There are over 50 reported 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 .
TNNT2 — Defects in the gene for cardiac troponin T (TNNT2), responsible for 4 to 15 percent of HCM cases, 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 — Mutations in the gene for cardiac troponin I (TNNI3), identified in 2 to 7 percent of HCM cases, have a disease penetrance of about 50 percent and may be associated with dilated or restrictive physiology [7,8]. Disease expression within a family may be extremely variable .
Rarer variants — Mutations 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 less than 5 percent of cases of HCM. Penetrance cannot be estimated given the limited data.
INDIVIDUAL 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, whether or not the genetic test was performed because of a family history of HCM (algorithm 1). Clinical evaluation for HCM 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 ambiguous. (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 that they should seek consultation regarding clinical evaluation for HCM and/or testing for the variant identified in the proband. (See 'Evaluation of family members' 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 being 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, and 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 family members' 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. As variants may be reclassified (either as pathogenic or benign) with emergence of new evidence over time, it is necessary to maintain surveillance of a gene database on a regular basis.
INDIVIDUAL WITH KNOWN HCM — Patients with HCM should be referred to a cardiologist for counseling and disease management. The diagnosis of HCM is based on clinical criteria and is not ruled out if genetic testing does not identify a sarcomere variant associated with HCM. Such patients may have variants that either were not tested in the specific gene panel used, or were not detected.
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 family members. Patients with HCM should be advised to inform family members to seek consultation for clinical testing and genetic counseling. (See 'Evaluation of family members' below.)
Pathogenic or likely pathogenic variant — Identification of a pathogenic or likely pathogenic variant does not impact management decisions for an individual with HCM. (See 'UpToDate topics' below.)
Variant of uncertain significance — A substantial proportion of patients with a clinical diagnosis of HCM will have a variant of uncertain significance (VUS) identified. Since it is not clear that the VUS is actually responsible for disease, these variants cannot be used for family screening to determine if other family members are at risk .
Variants may be reclassified (upgraded to pathogenic or downgraded to benign) as new evidence emerges. Some laboratories maintain surveillance of a gene database(s) on a regular basis and routinely provide updates, and others require a request. It is important to reevaluate the pathogenicity of a VUS during follow-up. This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a specialist, clinical geneticist, or genetic counselor. (See 'Locating a genetics expert' below.)
EVALUATION OF FAMILY MEMBERS — Since HCM is inherited in an autosomal dominant pattern, 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 for HCM 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 family member, those relatives who test negative for the identified variant can be reassured that they are unlikely to develop HCM. Those relatives who test positive for the identified pathogenic variant (when clinical testing does not indicate left ventricular [LV] 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 family members will not help determine if they are at risk of developing disease. For those family members, clinical surveillance for HCM should begin at the onset of puberty, or it can be considered earlier if the child has a high-risk family history or is participating in intense competitive sports. Any child with symptoms suggestive of HCM should be evaluated.
●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:
Hypertrophic cardiomyopathy: Medical therapy for heart
Hypertrophic cardiomyopathy: Medical management for non-heart failure symptoms
Hypertrophic cardiomyopathy: Nonpharmacologic treatment of left ventricular outflow tract obstruction
Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk
●General genetics concepts:
•Pathogenicity – (See "Secondary findings from genetic testing".)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•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)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
- Ingles J, Goldstein J, Thaxton C, et al. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med 2019; 12:e002460.
- Burns C, Bagnall RD, Lam L, et al. Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. Circ Cardiovasc Genet 2017; 10.
- Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998; 338:1248.
- Van Driest SL, Jaeger MA, Ommen SR, et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:602.
- Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107:2227.
- Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol 2007; 49:2419.
- Mogensen J, Murphy RT, Kubo T, et al. Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:2315.
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Pathogenic||Associated with disease risk|
|Likely pathogenic||>90% likelihood of disease risk association|
|Variant of uncertain significance (VUS)||Available data do not allow classification into one of the other categories|
|Likely benign||>90% likelihood that variant is not associated with disease risk|
|Benign||Not associated with disease risk|
- Population data (allele frequency; prevalence of variant in affected individuals versus controls)
- Computational data (predicted effect on protein sequence or function)
- Functional data (functional studies show or do not show deleterious effect)
- Segregation data (variant segregates with disorder in families)
Supported by an unrestricted educational grant from AncestryHealth®.
|Disease-causing||Prevalence in patients with HCM|
|Cardiac myosin-binding protein C gene||MYBPC3||Up to 30%|
|Cardiac beta-myosin heavy chain gene||MYH7||Up to 25%|
|Cardiac troponin T gene||TNNT2||4 to 15%|
|Cardiac troponin I gene||TNNI3||2 to 7%|
|Myosin regulatory light chain gene||MYL2||Rare|
|Myosin essential light chain gene||MYL3||Rare|
|Alpha-cardiac actin gene||ACTC1||Rare|
|Tropomyosin 1 gene||TPM1||Rare|
|Cardiac troponin C gene||TNNC1|
|Junctophilin 2 gene||JPH2|
|Cysteine and glycine rich protein 3 gene||CSRP3|
* Risk genes for HCM include MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1, and TPM1.
¶ Ensure that the genetic testing is performed properly, the patient identification is correct, and the interpretation of pathogenicity is accurate based on the most recent data analysis. Pathogenic and likely pathogenic variants are treated the same for purposes of surveillance and risk-reduction interventions. Gene tests may indicate a benign or likely benign variant or a VUS, though such results are often not reported. VUSs lack sufficient information from clinical and bench research to be classified as pathogenic or benign. Continue to seek updated interpretation of pathogenicity periodically.
Δ Consider cardiac MRI if the echocardiogram is of nondiagnostic quality or if the ECG is abnormal and the echocardiogram is normal or ambiguous.
◊ HCM is diagnosed by the presence of LVH (≥15 mm thickening anywhere in the LV wall) in the absence of any other identifiable cause (eg, hypertension or valve disease).
§ Specific activity restrictions to be based on shared decision-making between clinician and patient.
¥ Some experts advise initial genetic testing.
‡ Every 1 to 2 years for adolescents.
† If initial gene test did not include the variant of the affected FDR, repeat testing to include that variant.
Contributor DisclosuresMartin S Maron, MDConsultant/Advisory Boards: Celltrion [Hypertrophic cardiomyopathy (Cebenzoline)]; iRhythm [Monitoring (Heart monitoring device)]; Cytokinetics [Hypertrophic cardiomyopathy].William J McKenna, MDNothing to discloseJennifer S Tirnauer, MDNothing to discloseSusan B Yeon, MD, JD, FACCNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.