Nonsyndromic Hypertrophic Cardiomyopathy Overview
Allison L Cirino, MS, CGC, Nadine Channaoui, MS, CGC, and Carolyn Ho, MD.
Author Information and AffiliationsInitial Posting: August 5, 2008; Last Update: March 6, 2025.
Estimated reading time: 26 minutes
1. Clinical Characteristics of Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH) with a maximum left ventricular (LV) wall thickness ≥15 mm in adults or an LV wall thickness z score >3 in children [Ommen et al 2024]. If there is a family history of a clinical or molecular diagnosis of HCM, a maximum LV wall thickness ≥13-14 mm supports the diagnosis. Such LVH occurs in a nondilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload or storage/infiltrative disorders.
The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac MRI.
While asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy vary. LVH can be concentric, confined to other walls, or involving the LV apex.
Findings on transthoracic echocardiography may also include:
Although LVH and a clinical diagnosis of HCM often become apparent during adolescence or early adulthood, onset can be earlier (in infancy and childhood) or later in life. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope.
Variability and progression. The clinical manifestations of HCM are highly variable, ranging from asymptomatic LVH to arrhythmias (atrial fibrillation as well as malignant ventricular arrhythmias) to refractory heart failure. Moreover, disease expression and penetrance can vary even within the same family.
Left ventricular outflow tract obstruction (LVOTO) is one of the most characteristic features of HCM. At least 25%-30% of persons with HCM have detectable intracavitary obstruction (defined as peak gradient ≥30 mm Hg) at rest or with provocation (e.g., reduction of preload or afterload) [Maron 2003, Elliott et al 2014, Ho et al 2018, Maurizi et al 2023]. LVOTO gradients fluctuate in response to a variety of factors (e.g., preload, afterload, and heart rate). The degree of obstruction does not strictly correlate with the severity of symptoms or risk for sudden cardiac death (SCD). High gradients may be well tolerated but, over medium to long term, often lead to limiting symptoms and may be associated with other adverse impacts, including atrial fibrillation and worsened functional capacity [Maurizi et al 2023, Ahluwalia et al 2025].
Individuals with HCM are at an increased risk for atrial fibrillation (AF), which can have significant morbidity due to increased risk of thromboembolism and symptomatic deterioration. The prevalence of AF increases with age and duration of disease. The overall prevalence of AF in individuals with HCM is ~20%, but prevalence is ~60% by age 60 years for individuals diagnosed with HCM by age 40 years [Elliott et al 2014, Rowin et al 2017, Ho et al 2018]. In one series, 6% of individuals with HCM and AF had thromboembolic strokes [Rowin et al 2017].
Left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction (LVEF) <50%, is seen in approximately 8% of individuals with HCM [Marstrand et al 2020]. Individuals with HCM and LVSD have worse survival when compared to individuals with HCM and preserved ejection fraction [Marstrand et al 2020, Rowin et al 2020]. Worse outcomes with LVSD were predicted in individuals with presence of multiple pathogenic / likely pathogenic variants in one of the genes encoding a component of the sarcomere, AF, and/or LVEF <35% [Marstrand et al 2020].
SCD, most likely related to ventricular tachycardia / ventricular fibrillation, is an important but relatively rare consequence of HCM. In a large cohort of individuals with HCM, 6% experienced SCD, resuscitated cardiac arrest, or treatment with implantable cardioverter-defibrillator (ICD) [Ho et al 2018].
SCD occurs most often in adolescents or young adults but may occur at any age and the risk persists throughout life, particularly for persons with HCM caused by a
pathogenic variant in one of the genes encoding a component of the sarcomere.
Life span. Compared to the US general population, the mortality rate in individuals with HCM is approximately threefold higher, but the mortality rate in younger individuals with HCM (age 20-29 years) is as much as fourfold higher. SCD accounts for 16% of deaths in individuals with HCM [Ho et al 2018].
Penetrance
Penetrance is estimated to be 50%-62% in at-risk relatives who were heterozygous for the familial HCM-related pathogenic variant [Lorenzini et al 2020, Christian et al 2022, Topriceanu et al 2024]. A meta-analysis among relatives with the known familial pathogenic variant found variability in penetrance by gene: MYL3 (~32%), CSRP3 (38%), TPM1 (~49%), ALPK3 (50%), MYBPC3 (~55%), TNNT2 (~62%), TNNI3 (~60%), MYH7 (~64%), MYL2 (~65%), ACTC1 (69%) [Topriceanu et al 2024].
2. Genetic Causes of Nonsyndromic Hypertrophic Cardiomyopathy
Pathogenic variants in one of the genes encoding a component of the sarcomere (i.e., sarcomeric pathogenic variant) are the predominant cause of nonsyndromic hypertrophic cardiomyopathy (HCM) [Ingles et al 2019]; MYBPC3 and MYH7 are the most commonly involved genes. Identifying a sarcomeric pathogenic variant has prognostic value. In a large multicenter registry, individuals with a sarcomeric pathogenic variant were shown to have earlier onset and higher incidence of adverse outcomes compared to those without a sarcomeric pathogenic variant [Ho et al 2018]. Individuals with ≥2 sarcomeric pathogenic variants were reported to have a higher risk for transplantation / left ventricular (LV) assist device (HR: 7.5, 95% CI: 2.7-20.5; compared to individuals with one sarcomeric pathogenic variant) and stroke [Ho et al 2018].
The Clinical Genome Resource (ClinGen) HCM Gene Curation Expert Panel has classified HCM genes using the ClinGen framework for the strength of their relationship with monogenic, nonsyndromic HCM (see Table 1). A summary of the data curated for each gene can be accessed at ClinGen Hypertrophic Cardiomyopathy Gene-Disease Validity. Approximately 30% of individuals with nonsyndromic HCM will have a pathogenic or likely pathogenic variant identified in current genetic testing. That percentage is approximately 60% in individuals with a family history of nonsyndromic HCM [Alfares et al 2015, Ireland & Ho 2024, Ommen et al 2024].
Note: Pathogenic variants identified in genes classified by ClinGen as having only "moderate" or "limited" evidence supporting a causal relationship with HCM should be interpreted with thorough consideration of genotype-phenotype correlation. For example, presence or absence of a pathogenic variant in a gene where causation of HCM has only limited evidence may not be clinically informative in phenotypically unaffected family members.
Table 1.
Nonsyndromic Hypertrophic Cardiomyopathy Genes
View in own window
AD = autosomal dominant; AR = autosomal recessive; ARVC = arrhythmogenic right ventricular cardiomyopathy; CPVT = catecholaminergic polymorphic ventricular tachycardia; DCM = dilated cardiomyopathy; LVNC = left ventricular noncompaction; MT = mitochondrial; MOI = mode of inheritance
- 1.
Genes are ordered first by validity classification and then alphabetically.
- 2.
- 3.
Allelic disorders = other phenotypes caused by pathogenic variants in the same gene
- 4.
PLN and ACTN2 were curated for intrinsic cardiomyopathy given their association with a spectrum of cardiac phenotypes, including isolated left ventricular hypertrophy (LVH) and HCM.
- 5.
There are multiple Dutch founder pathogenic variants in MYBPC3, including c.2373_2374insG, c.2827C>T, c.2864_2865delCT, c.3776delA, c.481C>T, c.551dupT, and c.927-2A>G (NM_000256.3). There is one MYBPC3 Amish founder pathogenic variant, NM_000256.3:c.3330+2T>G. There is one MYBPC3 French Canadian founder pathogenic variant, NM_000256.3:c.551dupT.
3. Differential Diagnosis of Nonsyndromic Hypertrophic Cardiomyopathy
Other causes of hypertrophic cardiomyopathy (HCM) include acquired left ventricular hypertrophy and syndromic HCM.
Acquired Left Ventricular Hypertrophy (LVH)
Acquired LVH can be pathologic, occurring in response to pressure overload (e.g., systemic hypertension, aortic stenosis). This type of adverse remodeling can lead to diastolic abnormalities and heart failure. Physiologic hypertrophy (athlete's heart) may result from rigorous athletic training, particularly in sports with a high static / strength building component of exercise. Such training may result in increased left ventricular wall thickness accompanied by increased left ventricular cavity size. This type of remodeling is thought to be adaptive and not associated with adverse consequences. Both pathologic and physiologic forms of acquired hypertrophy can regress if the underlying stimulus is removed (e.g., by adequate treatment of high blood pressure or a period of detraining for an athlete).
Syndromic HCM
Table 2.
Syndromic Hypertrophic Cardiomyopathy – A Select List
View in own window
- 1.
The RASopathies are a group of syndromes that have overlapping clinical features resulting from a common pathogenetic mechanism [Tidyman & Rauen 2009].
- 2.
Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.
4. Evaluation Strategy to Identify (when Possible) the Genetic Cause of Hypertrophic Cardiomyopathy
Establishing a specific genetic cause of nonsyndromic hypertrophic cardiomyopathy (HCM):
Can aid in discussions of prognosis (which are beyond the scope of this
GeneReview) and
genetic counseling;
Usually involves a family history and
genomic/genetic testing.
Family history. A three-generation family history should be taken, with attention to relatives with manifestations of heart failure, HCM, cardiac transplantation, unexplained or sudden death (particularly in relatives age <40 years), cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
A multigene panel that includes some or all of the genes listed in
Table 1 is most likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype.
The majority of causal pathogenic variants in nonsyndromic HCM are
missense variants, except those in
MYBPC3, which are often frameshift or
nonsense variants resulting in protein truncation. Depending on the sequencing method used and
copy number variant detection tools,
exon or whole-
gene deletions/duplications may not be detected. Studies that have included
deletion/duplication analysis have found that large deletions and duplications are not a major cause of nonsyndromic HCM [
Bagnall et al 2010,
Ceyhan-Birsoy et al 2015,
Bagnall et al 2018]. Single-exon or multiexon deletions or duplications that are potentially contributory/causative of nonsyndromic HCM have been reported in genes
FHOD3 [
Ochoa et al 2020],
MYBPC3 [
Chanavat et al 2012,
Janin et al 2020,
Nfonsam et al 2020],
MYH7 [
Marian et al 1992], and
PLN [
Mademont-Soler et al 2017] in a few individuals with nonsyndromic HCM.
Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom
phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a
multigene panel that also includes deletion/duplication analysis is recommended.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Comprehensive
genomic testing (which does not require the clinician to determine which
gene[s] are likely involved) may be considered.
Exome sequencing is most commonly used;
genome sequencing is also possible.
For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
5. Management of Hypertrophic Cardiomyopathy
Clinical practice guidelines for hypertrophic cardiomyopathy (HCM) have been published [Ommen et al 2024] (full text).
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HCM, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Evaluations Following Initial Diagnosis
View in own window
| System/Concern | Evaluation | Comment |
|---|
|
Cardiac
| Cardiology eval EKG Echocardiogram
| At the time of diagnosis, regardless of age |
|
Genetic counseling
| By genetics professionals 1 | To obtain a pedigree (at least 3 generations) & inform affected persons & their families re nature, MOI, & implications of HCM to facilitate medical & personal decision making |
- 1.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended [Ommen et al 2024]. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).
Table 4.
Nonsyndromic Hypertrophic Cardiomyopathy: Treatment of Manifestations
View in own window
| Manifestation/Concern | Treatment |
|---|
|
Symptomatic nonobstructive hypertrophic cardiomyopathy w/preserved ejection fraction
| Pharmacologic therapy to alleviate symptoms, incl beta-blockers, calcium channel blockers, & oral diuretics |
|
Symptomatic LVOTO
| Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy & consideration of calcium channel blockers, disopyramide, & myosin inhibitors (adults only), as appropriate Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy.
|
|
Ventricular arrhythmia
| Assessment of risk for sudden cardiac death & appropriate use of primary prevention ICDs Antiarrhythmic drug therapy for refractory or symptomatic arrhythmias Consideration of electrophysiologic studies & ablation therapy for refractory or symptomatic arrhythmias
|
|
Atrial fibrillation
| Oral anticoagulation regardless of standard algorithms to predict thromboembolic risk |
|
Heart failure w/systolic dysfunction
| Standard treatment, incl careful fluid & volume mgmt Assessment & mgmt of other causes of systolic dysfunction Timely consideration of cardiac transplantation or mechanical circulatory support in those w/progressive symptoms Guideline-based medical therapy for heart failure w/reduced ejection fraction & consideration of ICD placement for persistent LVEF <50%
|
ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; LVOTO = left ventricular outflow tract obstruction
Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended for individuals with a clinical diagnosis of nonsyndromic HCM [Ommen et al 2024].
Table 5.
Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Surveillance
View in own window
| System/Concern | Evaluation | Frequency 1 |
|---|
|
Cardiac
| Cardiology eval
Echocardiogram |
|
| Cardiac MRI | May be used in select circumstances (i.e., when echocardiogram is inconclusive or to provide additional information for SCD risk assessment) |
|
| Every 1-2 yrs beginning at diagnosis (regardless of age) |
| Extended ambulatory monitoring | May be warranted if symptoms emerge & for those at higher risk for AF |
| Exercise stress testing | Should be used to assess latent LVOTO for all persons w/o resting obstruction, particularly if symptoms are present As needed to assess functional decline, or every 2-3 yrs w/o evidence of functional decline in adults & older children (age >~7-8 yrs)
|
AF = atrial fibrillation; LVOTO = left ventricular outflow tract obstruction; SCD = sudden cardiac death
- 1.
Screening interval may be modified based on symptom development and/or family history.
Agents/Circumstances to Avoid
Avoid dehydration; in general use caution to stay adequately hydrated, particularly when exercising or when insensible losses are increased.
Comorbidities such as hypertension, obesity, and sleep apnea may exacerbate clinical manifestations and, therefore, should be optimally managed.
Evaluation and Surveillance of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of cardiac surveillance and treatment. Evaluations can include the following:
Molecular genetic testing if the HCM-related
pathogenic variant(s) in the family are known
Those identified as having a
familial HCM-related
pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years.
In general, family members in whom the
familial HCM-related
pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related
gene [
Ho et al 2018], thorough individualized risk assessment through clinical, genetic, and family history analysis is warranted to determine if discharge from high-risk cardiac surveillance is appropriate.
If the HCM-related
pathogenic variant in the family is not known or the relative has not undergone genetic testing, physical examination, EKG, and echocardiography every two to three years for children and adolescents (starting before puberty) and every three to five years for adults is recommended [
Ommen et al 2024]. The
penetrance of clinical manifestations of HCM is age dependent; a normal cardiac evaluation does not exclude the possibility of developing HCM.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Pregnancy is generally well tolerated in individuals with nonsyndromic HCM, and maternal mortality is low (0.2%) [Moolla et al 2022]. Reports of cardiac events in pregnancy range from 9%-23% of pregnancies, with events most often occurring in the third trimester [Goland et al 2017, Choi et al 2024]. Prenatal care should be coordinated by a cardiologist and obstetrician (or maternal-fetal medicine specialist) if a pregnancy is deemed high risk to review medications and establish a surveillance and delivery plan.
Therapies Under Investigation
There are currently many novel therapies for nonsyndromic HCM under investigation. The cardiac myosin inhibitor (CMI) mavacamten received FDA approval for use in symptomatic obstructive HCM in April 2022. CMI use for nonobstructive HCM (NCT06081894, NCT05582395) and treatment of younger age groups (NCT06253221) is currently under investigation.
Other therapeutic agents are also under investigation in those with obstructive and nonobstructive HCM. These include both novel agents (NCT06347159) and established medications that have not been previously assessed in individuals with HCM (e.g., sotagliflozin; NCT06481891).
A gene therapy trial is currently under way for symptomatic adults with MYBPC3-related HCM (NCT05836259).
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
6. Genetic Counseling of Family Members of an Individual with Nonsyndromic Hypertrophic Cardiomyopathy
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Autosomal Dominant Inheritance – Risk to Family Members
Parents of a proband
Some individuals diagnosed with
autosomal dominant nonsyndromic HCM have an affected parent.
Some individuals diagnosed with
autosomal dominant nonsyndromic HCM have the disorder as the result of a
de novo pathogenic variant. The proportion of individuals with autosomal dominant nonsyndromic HCM caused by a
de novo pathogenic variant is unknown.
An individual with nonsyndromic HCM may have pathogenic variants in more than one HCM-related
gene. In a study involving 1,279 individuals with nonsyndromic HCM of known genetic cause, 34 (~3%) individuals had pathogenic /
likely pathogenic variants in two or more genes that encode a component of the sarcomere [
Ho et al 2018].
If the
proband appears to be the only family member with nonsyndromic HCM (i.e., a
simplex case), recommendations for the evaluation of the parents of the proband include
molecular genetic testing (if the HCM-related
pathogenic variant has been identified in the proband), physical examination, EKG, and echocardiogram by a cardiologist familiar with HCM. Note: Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced
penetrance. Therefore,
de novo occurrence of a pathogenic variant in an HCM-related
gene in the proband cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is
heterozygous for the HCM-related pathogenic variant identified in the proband).
If the HCM-related
pathogenic variant identified in the
proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents:
If a parent of the
proband is affected and/or is known to have the
autosomal dominant nonsyndromic HCM-related
pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
Sibs who inherit an
autosomal dominant nonsyndromic HCM-related
pathogenic variant have an increased risk of developing nonsyndromic HCM. Penetrance is estimated to be 50%-62% in at-risk relatives who are
heterozygous for a
familial HCM-related pathogenic variant (see
Penetrance). Because disease expression and
penetrance can vary even within the same family, clinical severity and age of onset cannot be predicted in sibs who inherit a nonsyndromic HCM-related pathogenic variant.
If the
proband represents a
simplex case and the parents are clinically unaffected (based on appropriate cardiac evaluation) but their genetic status is unknown, sibs are still presumed to be at increased risk for nonsyndromic HCM because of the possibility of reduced
penetrance in a
heterozygous parent or parental
gonadal mosaicism.
Offspring of a proband. Each child of an individual with autosomal dominant nonsyndromic HCM has a 50% chance of inheriting the pathogenic variant and therefore being at risk for developing nonsyndromic HCM.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has an autosomal dominant nonsyndromic HCM-related pathogenic variant, the parent's family members may be at risk.
Autosomal Recessive Inheritance – Risk to Family Members
Parents of a proband
If a
pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the
proband occurred as a
de novo event in the proband or as a
postzygotic de novo event in a mosaic parent [
Jónsson et al 2017]. If the proband appears to have
homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
Typically, risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, individuals who are
heterozygous for a
pathogenic variant in
ALPK3 may be at increased risk of developing cardiomyopathy in adulthood [
Almomani et al 2016].
Sibs of a proband
If both parents are known to be
heterozygous for an
autosomal recessive nonsyndromic HCM-related
pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the
familial HCM-related pathogenic variants.
Typically, the risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, however, individuals who are
heterozygous for a
pathogenic variant in
ALPK3 may be at increased risk of developing cardiomyopathy in adulthood [
Almomani et al 2016].
Offspring of a proband. The offspring of an individual with autosomal recessive nonsyndromic HCM are obligate heterozygotes (carriers) for a nonsyndromic HCM-related pathogenic variant.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a nonsyndromic HCM-related pathogenic variant.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Children's Cardiomyopathy Foundation
Hypertrophic Cardiomyopathy Association (HCMA)
Phone: 973-983-7429
Email: support@4hcm.org
American Heart Association
Phone: 800-242-8721
Cardiomyopathy UK
United Kingdom
Phone: 0800 018 1024 (UK only)
Email: contact@cardiomyopathy.org
Sudden Arrhythmia Death Syndromes (SADS) Foundation
Phone: 801-948-0654; 801-272-3023
Email: sads@sads.org
Chapter Notes
Revision History
6 March 2025 (sw) Comprehensive update posted live
6 June 2019 (ha) Comprehensive update posted live
16 January 2014 (me) Comprehensive update posted live
5 August 2008 (me) Review posted live
11 June 2007 (ac) Original submission
References
Published Guidelines / Consensus Statements
Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81. [
PubMed]
Elliott PM ,Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-79. [
PubMed]
Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with
familial sudden cardiac death syndrome. Europace. 2010;12:1156-75. [
PubMed]
Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani JA, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JJ, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu SS, Saberi S, Semsarian C, Times S, Waldman CB. 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. J Am Coll Cardiol. 2024;83:2324-405. [
PubMed]
Literature Cited
Ahluwalia
M, Liu
J, Olivotto
I, Parikh
V, Ashley
EA, Michels
M, Ingles
J, Lampert
R, Stendahl
JC, Colan
SD, Abrams
D, Pereira
AC, Rossano
JW, Ryan
TD, Owens
AT, Ware
JS, Saberi
S, Helms
AS, Day
S, Claggett
B, Ho
CY, Lakdawala
NK. The clinical trajectory of NYHA functional class I patients with obstructive hypertrophic cardiomyopathy.
JACC Heart Fail.
2025;13:332-43.
[
PubMed: 39520446]
Alfares
AA, Kelly
MA, McDermott
G, Funke
BH, Lebo
MS, Baxter
SB, Shen
J, McLaughlin
HM, Clark
EH, Babb
LJ, Cox
SW, DePalma
SR, Ho
CY, Seidman
JG, Seidman
CE, Rehm
HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.
Genet Med.
2015; 17:880-8.
[
PubMed: 25611685]
Almomani
R, Verhagen
JMA, Herkert
JC, Brosens
E, van Spaedonck-Zwarts
KY, Asimaki
A, van der Zwaag
PA. Frohn-Mulder IME, Bertollo-Avella AM, Boven LG, van Slegtenhorst MA, van der Smagt JJ, van IJcken WFJ, Timmer B, van Stuijvenberg M, Verdijk RM, Saffitz JE, du Plessis FA, Michels M, Hofstra RM, Sinke RJ, van Tintelen JP, Wessels MW, Jongbloed JD, van de Laar IM. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy.
J Am Coll Cardiol.
2016; 67: 515-25.
[
PubMed: 26846950]
Bagnall
RD, Ingles
J, Dinger
ME, Cowley
MJ, Ross
SB, Minoche
AE, Lal
S, Turner
C, Colley
A, Rajagopalan
S, Berman
Y, Ronan
A, Fatkin
D, Semsarian
C. Whole genome sequencing improves outcomes of genetic testing in patients with hypertrophic cardiomyopathy.
J Am Coll Cardiol.
2018;72:419-29.
[
PubMed: 30025578]
Bagnall
RD, Yeates
L, Semsarian
C. The role of large gene deletions and duplications in MYBPC3 and TNNT2 in patients with hypertrophic cardiomyopathy.
Int J Cardiol.
2010;145:150-3.
[
PubMed: 19666196]
Bagnall
RD, Weintraub
RG, Ingles
J, Duflou
J, Yeates
L, Lam
L, Davis
AM, Thompson
T, Connell
V, Wallace
J, Naylor
C, Crawford
J, Love
DR, Hallam
L, White
J, Lawrence
C, Lynch
M, Morgan
N, James
P, du Sart
D, Puranik
R, Langlois
N, Vohra
J, Winship
I, Atherton
J, McGaughran
J, Skinner
JR, Semsarian
C. A prospective study of sudden cardiac death among children and young adults.
N Engl J Med.
2016;374:2441-52.
[
PubMed: 27332903]
Ceyhan-Birsoy
O, Pugh
TJ, Bowser
MJ, Hynes
E, Frisella
AL, Mahanta
LM, Lebo
MS, Amr
SS, Funke
BH. Next generation sequencing-based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies.
Mol Genet Genomic Med.
2015;4:143-51.
[
PMC free article: PMC4799872] [
PubMed: 27066507]
Chanavat
V, Seronde
MF, Bouvagnet
P, Chevalier
P, Rousson
R, Millat
G. Molecular characterization of a large MYBPC3 rearrangement in a cohort of 100 unrelated patients with hypertrophic cardiomyopathy.
Eur J Med Genet.
2012;55:163-6.
[
PubMed: 22314326]
Choi
WY, Park
KT, Kim
HM, Cho
JH, Nam
G, Hong
J, Kang
D, Lee
J. Pregnancy related complications in women with hypertrophic cardiomyopathy: a nationwide population-based cohort study.
BMC Cardiovasc Disord.
2024;24:268.
[
PMC free article: PMC11106953] [
PubMed: 38773383]
Christian
S, Cirino
A, Hansen
B, Harris
S, Murad
AM, Natoli
JL, Malinowski
J, Kelly
MA. Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis.
Open Heart.
2022;9:e001815.
[
PMC free article: PMC8987756] [
PubMed: 35387861]
Eckart
RE, Shry
EA, Burke
AP, McNear
JA, Appel
DA, Castillo-Rojas
LM, Avedissian
L, Pearse
LA, Potter
RN, Tremaine
L, Gentlesk
PJ, Huffer
L, Reich
SS, Stevenson
WG. Sudden death in young adults: autopsy-based series of a population undergoing active surveillance.
J Am Coll Cardiol.2011; 58: 1254-61.
[
PubMed: 21903060]
Elliott
PM, Anastasakis
A, Borger
MA, Borggrefe
M, Cecchi
F, Charron
P, Hagege
AA, Lafont
A, Limongelli
G, Mahrholdt
H, McKenna
WJ, Mogensen
J, Nihoyannopoulos
P, Nistri
S, Pieper
PG, Pieske
B, Rapezzi
C, Rutten
FH, Tillmanns
C, Watkins
H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy.
Eur Heart J.
2014; 35:2733-79.
[
PubMed: 25173338]
Finocchiaro
G, Papadakis
M, Tanzarella
G, Dhutia
H, Miles
C, Tome
M, Behr
ER, Sharma
S, Sheppard
MN. Sudden death can be the first manifestation of hypertrophic cardiomyopathy: data from a United Kingdom pathology registry.
JACC Clin Electrophysiol.
2019; 5: 252-4.
[
PubMed: 30784699]
Forissier
JF, Richard
P, Briault
A, Ledeuil
C, Dubourg
O, Charbonnier
B, Carrier
L, Moraine
C, Boone
G, Komajda
M, Schwartz
K, Hainque
B. First description of germline mosaicism in familial hypertrophic cardiomyopathy.
J Med Genet.
2000; 37:132-4.
[
PMC free article: PMC1734529] [
PubMed: 10662815]
Goland
S, van Hagen
IM, Elbaz-Greener
G, Elkayam
U, Shotan
A, Merz
WM, Enar
SC, Gaisin
IR, Pieper
PG, Johnson
MR, Hall
R, Blatt
A, Roos-Hesselink
JW. Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac Disease (ROPAC).
Eur Heart J.
2017;38:2683-90.
[
PubMed: 28934836]
Guo
L, Torii
S, Fernandez
R, Braumann
RE, Fuller
DT, Paek
KH, Gadhoke
NV, Maloney
KA, Harris
K, Mayhew
CM, Zarpak
R, Stevens
LM, Gaynor
BJ, Jinnouchi
H, Sakamoto
A, Sato
Y, Mori
H, Kutyna
MD, Lee
PJ, Weinstein
LM, Collado-Rivera
CJ, Ali
BB, Atmakuri
DR, Dhingra
R, Finn
ELB, Bell
MW, Lynch
M, Cornelissen
A, Kuntz
SH, Park
JH, Kutys
R, Park
JE, Wang
L, Hong
SN, Gupta
A, Hall
JL, Kolodgie
FD, Romero
ME, Jeng
LJB, Mitchell
BD, Surve
D, Fowler
DR, Hong
CC, Virmani
R, Finn
AV. Genetic variants associated with unexplained sudden cardiac death in adult White and African American individuals.
JAMA Cardiol.
2021;6:1013-22.
[
PMC free article: PMC8173469] [
PubMed: 34076677]
Harmon
KG, Drezner
JA, Maleszewski
JJ, Lopez-Anderson
M, Owns
D, Prutkin
JM, Asif
IM, Klossner
D, Ackerman
MJ. Pathogenesis of sudden cardiac death in national collegiate athletic associated athletes.
Circ Arrhythm Electrophysiol.
2014; 7: 198-204.
[
PubMed: 24585715]
Ho
CY, Day
SM, Ashley
EA, Michels
M, Pereira
AC, Jacoby
D, Cirino
AL, Fox
JC, Lakdawala
NK, Ware
JS, Caleshu
CA, Helms
AS, Colan
SD, Girolami
F, Cecchi
F, Seidman
CE, Sajeev
G, Signorovitch
J, Green
EM, Olivotto
I, et al.
Genotype and lifetime burden of disease in hypertrophic cardiomyopathy. Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).
Circulation.
2018;138:1387-98.
[
PMC free article: PMC6170149] [
PubMed: 30297972]
Ingles
J, Goldstein
J, Thaxton
C, Caleshu
C, Corty
EW, Crowley
SB, Dougherty
K, Harrison
SM, McGlaughon
J, Milko
LV, Morales
A, Seifert
BA, Strande
N, Thomson
K, Peter van Tintelen
J, Wallace
K, Walsh
R, Wells
Q, Whiffin
N, Witkowski
L, Semsarian
C, Ware
JS, Hershberger
RE, Funke
B. Evaluating the clinical validity of hypertrophic cardiomyopathy genes.
Circ Genom Precis Med.
2019;12:e002460.
[
PMC free article: PMC6410971] [
PubMed: 30681346]
Ireland
CG, Ho
CY. Genetic testing in hypertrophic cardiomyopathy.
Am J Cardiol.
2024;212S:S4-S13.
[
PubMed: 38368035]
Janin
A, Chanavat
V, Rollat-Farnier
PA, Bardel
C, Nguyen
K, Chevalier
P, Eicher
JC, Faivre
L, Piard
J, Albert
E, Nony
S, Millat
G. Whole MYBPC3 NGS sequencing as a molecular strategy to improve the efficiency of molecular diagnosis of patients with hypertrophic cardiomyopathy.
Hum Mutat.
2020;41:465-75.
[
PubMed: 31730716]
Jónsson
H, Sulem
P, Kehr
B, Kristmundsdottir
S, Zink
F, Hjartarson
E, Hardarson
MT, Hjorleifsson
KE, Eggertsson
HP, Gudjonsson
SA, Ward
LD, Arnadottir
GA, Helgason
EA, Helgason
H, Gylfason
A, Jonasdottir
A, Jonasdottir
A, Rafnar
T, Frigge
M, Stacey
SN, Th Magnusson
O, Thorsteinsdottir
U, Masson
G, Kong
A, Halldorsson
BV, Helgason
A, Gudbjartsson
DF, Stefansson
K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
Nature.
2017;549:519-22.
[
PubMed: 28959963]
Lampert
R, Ackerman
MJ, Marino
BS, Burg
M, Ainsworth
B, Salberg
L, Tome Esteban
MT, Ho
CY, Abraham
R, Balaji
S, Barth
C, Berul
CI, Bos
M, Cannom
D, Choudhury
L, Concannon
M, Cooper
R, Czosek
RJ, Dubin
AM, Dziura
J, Eidem
B, Emery
MS, Estes
NAM, Etheridge
SP, Geske
JB, Gray
B, Hall
K, Harmon
KG, James
CA, Lal
AK, Law
IH, Li
F, Link
MS, McKenna
WJ, Molossi
S, Olshansky
B, Ommen
SR, Saarel
EV, Saberi
S, Simone
L, Tomaselli
G, Ware
JS, Zipes
DP, Day
SM; LIVE Consortium. Vigorous exercise in patients with hypertrophic cardiomyopathy.
JAMA Cardiol.
2023;8:595-605.
[
PMC free article: PMC10193262] [
PubMed: 37195701]
Lorenzini
M, Norrish
G, Field
E, Ochoa
JP, Cicerchia
M, Akhtar
MM, Syrris
P, Lopes
LR, Kaski
JP, Elliott
PM. Penetrance of hypertrophic cardiomyopathy in sarcomere protein mutation carriers.
J Am Coll Cardiol.
2020;76:550-9.
[
PMC free article: PMC7397507] [
PubMed: 32731933]
Mademont-Soler
I, Mates
J, Yotti
R, Espinosa
MA, Pérez-Serra
A, Fernandez-Avila
AI, Coll
M, Méndez
I, Iglesias
A, Del Olmo
B, Riuró
H, Cuenca
S, Allegue
C, Campuzano
O, Picó
F, Ferrer-Costa
C, Álvarez
P, Castillo
S, Garcia-Pavia
P, Gonzalez-Lopez
E, Padron-Barthe
L, Díaz de Bustamante
A, Darnaude
MT, González-Hevia
JI, Brugada
J, Fernandez-Aviles
F, Brugada
R. Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.
PLoS One.
2017;12:e0181465.
[
PMC free article: PMC5542623] [
PubMed: 28771489]
Marian
AJ, Yu
QT, Mares
A
Jr, Hill
R, Roberts
R, Perryman
MB. Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.
J Clin Invest.
1992;90:2156-65.
[
PMC free article: PMC443366] [
PubMed: 1361491]
Maron
BJ. Sudden death in young athletes.
N Engl J Med.
2003;349:1064-75
[
PubMed: 12968091]
Marstrand
P, Han
L, Day
SM, Olivotto
I, Ashley
EA, Michels
M, Pereira
AC, Wittekind
SG, Helms
A, Saberi
S, Jacoby
D, Ware
JS, Colan
SD, Semsarian
C, Ingles
J, Lakdawala
NK, Ho
CY; SHaRe Investigators. Hypertrophic cardiomyopathy with left ventricular systolic dysfunction: insights from the SHaRe registry.
Circulation.
2020;141:1371-83.
[
PMC free article: PMC7182243] [
PubMed: 32228044]
Maurizi
N, Chiriatti
C, Fumagalli
C, Targetti
M, Passantino
S, Antiochos
P, Skalidis
I, Chiti
C, Biagioni
G, Tomberli
A, Giovani
S, Coppini
R, Cecchi
F, Olivotto
I.
Real-world use and predictors of response to disopyramide in patients with obstructive hypertrophic cardiomyopathy.
J Clin Med.
2023;12:2725.
[
PMC free article: PMC10095445] [
PubMed: 37048808]
Moolla
M, Mathew
A, John
K, Yogasundaram
H, Alhumaid
W, Campbell
S, Windram
J. Outcomes of pregnancy in women with hypertrophic cardiomyopathy: a systematic review.
Int J Cardiol.
2022;359:54-60.
[
PubMed: 35427704]
Nfonsam
L, Huang
L, Carson
N, McGowan-Jordan
J, Beaulieu Bergeron
M, Goobie
S, Conacher
S, McCarty
D, Benson
L, Hewson
S, Zahavich
L, Sinclair-Bourque
E, Smith
A, Potter
R, Ghani
M, Bronicki
L, Jarinova
O.
ALU transposition induces familial hypertrophic cardiomyopathy.
Mol Genet Genomic Med.
2020;8:e951.
[
PMC free article: PMC6978237] [
PubMed: 31568709]
Ochoa
JP, Lopes
LR, Perez-Barbeito
M, Cazón-Varela
L, de la Torre-Carpente
MM, Sonicheva-Paterson
N, De Uña-Iglesias
D, Quinn
E, Kuzmina-Krutetskaya
S, Garrote
JA, Elliott
PM, Monserrat
L. Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy.
Clin Genet.
2020;98:86-90.
[
PubMed: 32335906]
Ommen
SR, Ho
CY, Asif
IM, Balaji
S, Burke
MA, Day
SM, Dearani
JA, Epps
KC, Evanovich
L, Ferrari
VA, Joglar
JA, Khan
SS, Kim
JJ, Kittleson
MM, Krittanawong
C, Martinez
MW, Mital
S, Naidu
SS, Saberi
S, Semsarian
C, Times
S, Waldman
CB. 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.
J Am Coll Cardiol.
2024;83:2324-405.
[
PubMed: 38727647]
Pelliccia
A, Lemme
E, Maestrini
V, Di Paolo
FM, Pisicchio
C, Di Gioia
G, Caselli
S. Does sport participation worsen the clinical course of hypertrophic cardiomyopathy? Clinical outcome of hypertrophic cardiomyopathy in athletes.
Circulation.
2018;137:531-3.
[
PubMed: 29378761]
Rowin
EJ, Hausvater
A, Link
MS, Abt
P, Gionfriddo
W, Wang
W, Rastegar
H, Estes
NAM, Maron
MS, Maron
BJ. Clinical profile and consequences of atrial fibrillation in hypertrophic cardiomyopathy.
Circulation.
2017;136:2420-36.
[
PubMed: 28916640]
Rowin
EJ, Maron
BJ, Carrick
RT, Patel
PP, Koethe
B, Wells
S, Maron
MS. Outcomes in patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction.
J Am Coll Cardiol.
2020;75:3033-43.
[
PubMed: 32553256]
Swain
WH, Burczak
DR, Karim
S, Pumarejo Medina
AM, Ismail
K, Alzate-Aguirre
M, Bos
JM, Noseworthy
PA, Newman
DB, Giudicessi
JR, Geske
JB, Ommen
SR, Ackerman
MJ, Arruda-Olson
AM, Siontis
KC. Resuscitated sudden cardiac arrest as the initial presentation of hypertrophic cardiomyopathy.
Circ Arrhythm Electrophysiol.
2024;17:e012970.
[
PubMed: 39429133]
Topriceanu
CC, Pereira
AC, Moon
JC, Captur
G, Ho
CY. Meta-analysis of penetrance and systematic review on transition to disease in genetic hypertrophic cardiomyopathy.
Circulation.
2024;149:107-23.
[
PMC free article: PMC10775968] [
PubMed: 37929589]
