GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of HCM is most often established when two-dimensional echocardiography detects LVH in a nondilated ventricle; it can also be established by pathognomonic histopathologic findings in cardiac tissue. Familial HCM without multisystem involvement is diagnosed by family history and molecular genetic testing of any of the 12 genes currently known to encode different components of the sarcomere for which testing is clinically available.
Management. Treatment of manifestations: medical management of diastolic dysfunction; medical or surgical management of ventricular outflow obstruction; restoration and maintenance of sinus rhythm in those with atrial fibrillation; implantable cardioverter-defibrillator (ICD) in survivors of cardiac arrest and those at high risk of cardiac arrest; medical treatment for heart failure and consideration for cardiac transplantation when necessary. Prevention of secondary complications: consideration of anticoagulation in those with persistent or paroxysmal atrial fibrillation to reduce the risk of thromboembolism; consideration of antibiotic prophylaxis when necessary; during the pregnancy of a woman with HCM, care by an experienced cardiologist and obstetrician trained in high-risk OB. Surveillance: reassessment of risk for SCD approximately once a year or more frequently based on clinical findings. Agents/circumstances to avoid: competitive endurance training, burst activities (e.g., sprinting), intense isometric exercise (e.g., heavy weight lifting), dehydration, hypovolemia (i.e., use diuretics with caution), and medications that decrease afterload (e.g., ACE-inhibitors, angiotensin receptor blockers, and other direct vasodilators). Testing of relatives at risk: Guidelines have been proposed for periodic screening of asymptomatic at-risk family members.
Genetic counseling. Familial HCM caused by mutation in one of the genes currently known to encode different components of the sarcomere is inherited in an autosomal dominant manner. Formal genetic counseling can be used to identify those family members of a proband who are at increased risk for HCM.
Hypertrophic cardiomyopathy (HCM) caused by mutation in one of the genes currently known to encode different components of the sarcomere is characterized by unexplained left ventricular hypertrophy (LVH) that develops in the absence of predisposing cardiac conditions (e.g., aortic stenosis) or cardiovascular conditions (e.g., long-standing hypertension). The clinical manifestations of HCM range from asymptomatic to progressive heart failure and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion) chest pain, palpitations, orthostasis, presyncope, and syncope.
Synonyms for HCM are hypertrophic obstructive cardiomyopathy (HOCM) and idiopathic hypertrophic subaortic stenosis (IHSS).
LVH most often becomes apparent during adolescence or young adulthood, possibly related to the onset of puberty; however, LVH caused by HCM can develop late in life [Niimura et al 2002], in infancy, and in childhood.
Diastolic dysfunction, as measured by tissue Doppler echocardiographic imaging, is a common finding in overt disease [Elliott & McKenna 2004] and also precedes both the development of LVH and symptoms in individuals who have a mutation in any one of the genes known to encode sarcomere proteins (i.e., “mutations in sarcomere genes”) [Nagueh et al 2001, Ho et al 2002]. This early diastolic dysfunction suggests that it may be a fundamental manifestation of HCM rather than a secondary consequence of LVH and altered myocardial compliance observed in established disease.
Approximately 25% of persons with HCM have detectable intracavitary obstruction at rest, but a much higher proportion may develop obstructive physiology with provocation [Maron et al 2003c, Elliott et al 2006, Maron et al 2006]. While individuals with significant outflow obstruction may be more symptomatic than those without outflow obstruction, the degree of outflow obstruction does not strictly correlate with the severity of symptoms. Furthermore, LV outflow tract and intracavitary gradients are dynamic, highly labile, and dependent on other physiologic variables, such as blood pressure and heart rate. Although evidence suggests that persons with outflow tract obstruction may have a higher risk of HCM-related death and symptom progression than those without outflow tract obstruction [Maron et al 2003c], high gradients may also be well tolerated over long periods of time.
Individuals with HCM are at an increased risk for atrial fibrillation (AF), which can be a significant cause of morbidity in adults:
Olivotto et al [2001] found a 22% prevalence of AF over nine years and found AF to be associated with increased risk for heart failure-related mortality, stroke, and functional limitations.
Kitaoka et al [2006] reported paroxysmal or persistent atrial fibrillation in 37% (51/137) of their older rural Japanese study population. From the time of initial diagnosis of AF, the one-year, three-year, and five-year survival rates were 92%, 86%, and 72%, respectively. In this study, 6/137 persons died of embolic stroke as a consequence of atrial fibrillation.
Approximately 10%-20% of individuals with HCM have a lifetime-increased risk for sudden cardiac death (SCD), most likely resulting from ventricular tachycardia/ ventricular fibrillation:
HCM is the leading single cause of SCD in competitive athletes in the US [Maron 2003], accounting for approximately one-third of such deaths.
Although sudden death occurs most often in adolescents or young adults, it may occur at any age. However, SCD is uncommon in young children.
SCD may be the first manifestation of disease [Maron et al 2000a]. Individuals with HCM who are at the highest risk for SCD may have at least 3%-5% annual risk for SCD [Maron 2002, Elliott & McKenna 2004], whereas individuals in the general HCM population have a 1% annual risk for SCD.
Early studies based on tertiary referral-based populations with HCM suggested a poor prognosis with estimated annual mortality rates of 4%-6%; however, subsequent studies on broader-based populations suggest that prognosis is typically more favorable with estimated annual mortality rates of 1%-3% and a normal life expectancy of 75+ years in an estimated 25% of individuals, the majority of whom have little functional disability [Maron et al 2003a, Maron et al 2003b, Elliott et al 2006].
Evaluation of prognosis and mortality in children with HCM revealed that the length of survival after establishing the diagnosis is shorter in those diagnosed before age one year than in those diagnosed after age one year; however, persons surviving until age one year have a 1% annual mortality rate regardless of the age at initial diagnosis [Colan et al 2007].
Figure 1
A. Normal heart histology
B. Heart with HCM showing disarray and increased fibrosis
C. Fibrosis can be better visualized with Masson trichrome staining in which fibrosis stains blue.
Images courtesy of Robert Padera, MD Brigham and Women’s Hospital Department of Pathology, Boston, MA.
Figure 2. Gross pathologic specimen from a patient with HCM, recovered at the time of cardiac transplantation
A. Note hypertrophy of the interventricular septum.
B. A friction plaque (arrow) is present in the LV outflow tract, anterior to the mitral valve. This indicates the presence of SAM and outflow tract obstruction.
Courtesy of Dr. Robert Padera, Department of Pathology, Brigham and Women’s Hospital.
, Figure 2):
Left ventricular hypertrophy (LVH) in a nondilated ventricle, most often established with two-dimensional echocardiography.
Note: (1) LVH should occur in the absence of other potential causes of cardiac hypertrophy (e.g., long-standing hypertension, aortic stenosis). (2) Although asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy varies and can include concentric and apical hypertrophy. (3) Findings on echocardiography may also include: (a) systolic anterior motion (SAM) of the mitral valve with associated left ventricular outflow tract obstruction and mitral regurgitation, (b) midventricular obstruction as a result of systolic cavity obliteration, and (c) diastolic dysfunction including restrictive physiology. (4) Cardiac MRI may be helpful when visualization of the left ventricle by echocardiography is suboptimal. (5) Although systolic function is typically preserved in HCM, 5%-10% of individuals with HCM progress to end-stage disease with impaired systolic function and, in some cases, left ventricular dilatation and regression of LVH. Without cardiac transplantation the annual mortality rate in this subset of individuals with HCM is estimated to be 11% [Harris et al 2006].
). Although scant amounts of disarray may be present in other cardiac diseases, the greater extent seen in HCM is distinctive. At the level of the whole organ, LVH is found (Figure 2). LVH commonly affects the interventricular septum (IVS) more prominently, although many different patterns of hypertrophy have been noted.Other findings that may suggest HCM but are not sufficiently sensitive to establish the diagnosis:
Physical examination, which may reveal:
A fourth heart sound (S4)
Prominent left ventricular apical impulse or lift
Brisk carotid upstroke that may be bifid
Note: (1) Left ventricular outflow tract or intracavitary obstruction is common, but can be variable and dynamic, requiring provocative maneuvers such as Valsalva, standing from squatting, and exercise for detection. (2) An apical holosystolic murmur of mitral regurgitation may be the result of SAM of the mitral valve or primary mitral valve disease.
Electrocardiogram (ECG). Most people with HCM have an abnormal ECG that can include the following:
A pattern consistent with LVH
A pattern consistent with left atrial enlargement
Prominent Q waves in inferior and lateral leads
Diffuse T-wave inversions
Note: (1) No one consistent ECG pattern is observed [Maron 2002]. (2) ECG abnormalities may precede echocardiographic evidence of LVH.
Physiologic hypertrophy (athlete’s heart) is a condition in which rigorously trained endurance athletes have left ventricular remodeling, including increased left ventricular wall thickness. Efforts to distinguish these conditions could include imposed deconditioning, during which the increased LV mass related to athlete’s heart should regress [Maron & Pelliccia 2006]. Evaluation of other indicators of cardiac pathology, including more extreme and/or asymmetric LVH, left atrial enlargement, ECG abnormalities, or evidence of diastolic dysfunction, support a diagnosis of HCM.
Adult-onset disease
Metabolic cardiomyopathy caused by mutations in PRKAG2 or LAMP2 should be considered when unexplained LVH is accompanied by preexcitation or if marked LVH is present in young males:
Mutations in PRKAG2 result in unexplained LVH and a high prevalence of conduction system disease. Inheritance is autosomal dominant.
Mutations in LAMP2 result in Danon disease associated with significant LVH and ventricular preexcitation with rapid progression of disease. Extracardiac features include skeletal myopathy and ophthalmologic manifestations including retinal dystrophy. Histopathologic inspection of muscle shows glycogen accumulation in vacuoles [Arad et al 2005]. Inheritance is X-linked with carrier females manifesting the cardiac phenotype.
Fabry disease results from deficient activity of the enzyme α-galactosidase (α-Gal A) and progressive lysosomal deposition in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually begins in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiovascular and/or cerebrovascular disease. In contrast, males with greater than 1% α-Gal A enzyme activity have a cardiac or renal variant phenotype. The cardiac variant phenotype usually presents in the sixth to eighth decade with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria without ESRD. Studies suggest that approximately 3%-10% of unexplained LVH in adult males may be caused by underlying Fabry disease [Sachdev et al 2002].
Early enzyme replacement therapy (ERT) may ameliorate or prevent development of many of the manifestations.
In males, the most efficient and reliable method for the diagnosis of Fabry disease is the demonstration of deficient α-Gal A enzyme activity in plasma, isolated leukocytes, and/or cultured cells. In females, molecular genetic testing of GLA using complete gene sequencing is the most reliable method to establish carrier status. Inheritance is X-linked.
Cardiac amyloidosis can be associated with LVH from accumulation of the amyloid protein, often resulting in a restrictive cardiomyopathy [Falk & Skinner 2000, Shah et al 2006]. The type of amyloidosis (primary [AL], familial, or senile), determined by the underlying amyloidogenic protein and molecular genetic testing, strongly influences prognosis.
AL (primary) amyloidosis results from a plasma cell dyscrasia and is composed of monoclonal immunoglobulin light chains. Often, there is associated renal involvement and a poor overall prognosis.
Transthyretin (TTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of nephropathy, cardiomyopathy, vitreous opacities, and CNS amyloidosis. Onset is usually in the third or fourth decade but may be later. Typically, sensory neuropathy starts in the lower extremities as paresthesia and hypesthesia of the feet and is followed by motor neuropathy within a few years. Autonomic neuropathy may be the first symptom; findings include orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive restrictive cardiomyopathy.
Sequence analysis of TTR, the only gene known to be associated with transthyretin (TTR) amyloidosis, detects more than 99% of disease-causing (amyloidogenic) mutations. Inheritance is autosomal dominant.
Childhood-onset disease
Inborn error of metabolism. Of 74 patients with inborn errors of metabolism, 25 (34%) had glycogen storage disease type II (GSD II; Pompe disease). GSD II is classified by age of onset, organ involvement, severity, and rate of progression. Classic infantile-onset Pompe disease may be apparent in utero but more often presents in the first month of life with hypotonia, generalized muscle weakness, cardiomegaly and HCM, feeding difficulties, failure to thrive, respiratory distress, and hearing loss. Without treatment by ERT, classic infantile-onset Pompe disease commonly results in death in the first year of life from progressive left ventricular outflow obstruction. The nonclassic variant of infantile-onset Pompe disease usually presents within the first year of life with motor delays and/or slowly progressive muscle weakness, typically resulting in death from ventilatory failure in early childhood. Cardiomegaly can be seen, but heart disease is not a major source of morbidity. Late-onset (i.e., childhood, juvenile, and adult-onset) Pompe disease is characterized by proximal muscle weakness and respiratory insufficiency without cardiac involvement.
Measurement of acid alpha-glucosidase (GAA) enzyme activity is diagnostic. Molecular genetic testing of GAA, the only gene known to be associated with GSD II, is clinically available. Inheritance is autosomal recessive.
Malformation syndrome. Of 77 individuals with a malformation syndrome, 60 (78%) had Noonan syndrome. Noonan syndrome is characterized by short stature, broad or webbed neck, unusual chest shape, developmental delay of variable degree, cryptorchidism, and characteristic facies. Congenital heart disease (including pulmonary valve stenosis, often with dysplasia; atrial and ventricular septal defects; branch pulmonary artery stenosis; and tetralogy of Fallot) occurs in 50%-80% of individuals. HCM, found in 20%-30% of individuals, may be present at birth or appear in infancy or childhood.
Diagnosis of Noonan syndrome is made on clinical grounds. Affected individuals have normal chromosome studies. In the four genes currently known to be associated with Noonan syndrome, mutations are identified in: PTPN11 (~50% of affected individuals), RAF1 (3%-17%), SOS1 (~10%), and KRAS (<5%). Inheritance is autosomal dominant. Between 25% and 70% of affected individuals have a de novo mutation.
Neuromuscular disorder. Of 64 individuals with neuromuscular disorders, 56 (88%) had Friedreich ataxia (FRDA). FRDA is characterized by slowly progressive ataxia with mean age of onset between age ten and 15 years and usually before age 25 years. FRDA is typically associated with depressed tendon reflexes, dysarthria, muscle weakness, spasticity in the lower limbs, optic nerve atrophy, scoliosis, bladder dysfunction, and loss of position sencse and vibration sense. HCM is present in two-thirds of individuals with FRDA. When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities. Although manifestations of cardiomyopathy usually occur in the later stages of the disease, in rare instances they may precede the onset of ataxia. Arrhythmias (especially atrial fibrillation) and congestive heart failure are the most common cause of death in FRDA.
Diagnosis of FRDA is based on molecular genetic testing of FXN. The FXN mutation that accounts for more than 96% of mutations in FRDA is a GAA triplet-repeat expansion in intron 1. Inheritance is autosomal recessive.
Figure 3. The sarcomere is the basic contractile unit of the cardiac myocyte. Cardiac contraction occurs when calcium binds the troponin complex (subunits I, C, and T) and α-tropomyosin and releases the inhibition of myosin-actin interactions by troponin I. ATPase activity and binding of actin by the globular myosin head result in conformational changes that bend the neck (also termed the lever arm) and result in the sliding of thick filaments in relation to thin filaments (solid arrows) to generate the power stroke [Kamisago et al 2000, with permission].
). More than 900 individual mutations have been identified [Genomics of Cardiovascular Development, Adaptation, and Remodeling].
| Locus Name | Gene Symbol | Protein Name | OMIM | % of HCM Caused by Mutations in This Gene | Molecular Genetic Test Availability for HMC 1 | Allelic Disorders 2 |
|---|---|---|---|---|---|---|
| CMH1 | MYH7 | Myosin heavy chain, cardiac muscle beta isoform | 160760 192600 | 40% | Clinical
 | DCM3, Laing distal myopathy |
| CMH4 | MYBPC3 | Myosin-binding protein C, cardiac-type | 600958 | 40% | Clinical
| DCM |
| CMH2 | TNNT2 | Troponin T, cardiac muscle | 115195 | 5% | Clinical
| DCM |
| CMH7 | TNNI3 | Troponin I, cardiac muscle | 191044 | 5% | Clinical
| DCM, restrictive cardiomyopathy |
| CMH3 | TPM1 | Tropomyosin 1 alpha chain | 115196 191010 | 2% | Clinical
| DCM |
| CMH10 | MYL2 | Myosin regulatory light chain 2, ventricular/cardiac muscle isoform | 160781 608758 | Unknown | Clinical
| |
| CMH8 | MYL3 | Myosin light polypeptide 3 | 160790 608751 | 1% | Clinical
| |
| ACTC1 | Actin, alpha cardiac muscle 1 | 102540 | Unknown | Clinical
| DCM | |
| CSRP3 | Cysteine and glycine-rich protein 3, muscle LIM protein | 600824 | Unknown | Research | ||
| CMH9 | TTN | Titin | 188840 | Clinical
| DCM, Udd distal myopathy | |
| MYH6 | Myosin heavy chain, cardiac muscle alpha isoform | 160710 | Research | DCM | ||
| TCAP | Telothonin | 604488 | Research | LGMD2G 4, DCM | ||
| Other genes implicated in HCM 5 | ||||||
| TNNC1 | Troponin C, slow skeletal and cardiac muscles | 191040 | Unknown | Clinical
| DCM | |
1. Per the GeneTests Laboratory Directory
2. Allelic disorders = other phenotypes caused by mutation in the same gene
3. DCM = dilated cardiomyopathy
4. LGMD = limb-girdle muscular dystrophy
5. The consensus of the GeneReview authors is that additional confirmatory data supporting pathogenicity for this gene is necessary.
When the diagnosis of LVH is established in an individual without other systemic involvement, the following approach can help determine if HCM was inherited or was caused by a de novo mutation in the proband. This approach is particularly relevant because a person with HCM may remain asymptomatic for years.
Family history. A detailed three- to four-generation family history should be obtained from relatives to assess the possibility of familial HCM. Attention should be directed to a history of any of the following in relatives: heart failure, HCM, cardiac transplantation, unexplained sudden death, unexplained cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease.
Any abnormal cardiovascular test results in a relative of a proband should be followed with a full cardiovascular assessment by a cardiologist familiar with HCM, as subtle changes in the context of familial disease may indicate a mild disease phenotype [McKenna et al 1997].
Note: No definitive genotype-phenotype correlations can be used to direct the approach to genetic testing.
Broader genotype-phenotype correlations have been attempted. Although in some cases the age of onset of hypertrophy may be associated with the underlying gene mutation, caution must be used in applying these generalizations to specific individuals and families as numerous exceptions have been noted.
Examples of broad genotype-phenotype correlations include the following:
MYH7 mutations have been associated with onset on the second decade of life
MYH7 mutation NP_000248.2:p.Arg403Gln (also known as NM_000257.2:c.1208G>A.) has been associated with an increased risk of sudden death.
MYBPC mutations have been associated with later onset in the fourth or fifth decade of life [Niimura et al 2002, Richard et al 2006].
TNNT2 mutations have been associated with mild LVH and increased risk of sudden death in some families [Richard et al 2006].
In children with LVH without systemic disease, a mutation in one of the genes encoding different components of the sarcomere was identified in 55% of the total: 49% of simplex cases (i.e., a single occurrence in a family) and 64% of familial cases. This prevalence of mutations in genes encoding different components of the sarcomere is essentially identical to that found in individuals with adult/adolescent HCM [Morita et al 2008]. Although most mutations were identified in MYH7 and MYBPC3, the proportion of MYBPC3 missense mutations was higher in those with childhood-onset than in those with adult-onset disease, in which most MYBPC3 mutations result in frameshifts. However, given the similarity in the prevalence and distribution of causal gene mutations, it remains unclear what underlies early-onset versus late-onset disease.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Familial hypertrophic cardiomyopathy (HCM) caused by mutation in one of the genes currently known to encode different components of the sarcomere is inherited in an autosomal dominant manner.
Parents of a proband
Some individuals diagnosed as having familial HCM have an affected parent.
A proband with familial HCM may also have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include echocardiogram, ECG, and physical examination by a cardiologist familiar with familial HCM. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of the possibility of incomplete penetrance and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate diagnostic evaluations have been performed.
Note: Although some individuals diagnosed with familial HCM have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
Sibs of a proband
The risk to sibs depends on the genetic status of the proband's parents.
If a parent of the proband is affected the risk to the sibs of inheriting the disorder is approximately 50%.
If a parent of the proband is shown to have a disease-causing mutation, the risk to the sibs of inheriting the allele is 50%. However, the clinical severity and age of onset cannot be predicted from the mutation.
When the parents are clinically unaffected and the disease-causing mutation is not known in the family, the risk to the sibs of a proband may be increased over the general population risk, but cannot be accurately estimated.
If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is extremely low but may be greater than that of the general population because of the possibility of germline mosaicism.
Offspring of a proband
Each child of an individual with familial HCM has a 50% chance of inheriting the mutation.
If a child inherits a disease-causing mutation there is a greater than 90% chance that the child will develop clinically evident HCM, although the severity and age of onset cannot be predicted.
Determining the mode of inheritance. Because cases have been reported where more than one mutation in a gene encoding a sarcomere protein has been identified in a single individual, determining the mode of inheritance is critical for accurate risk assessment of other family members [Richard et al 2006].
See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Testing of at-risk asymptomatic adult relatives of individuals with familial HCM is possible after molecular genetic testing has identified the disease-causing mutation in the proband. Such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing, but will identify family members who require serial clinical follow-up to assess for phenotypic conversion and allow reassurance of family members who are not at risk.
Testing of asymptomatic individuals younger than age 18 years requires careful consideration of the potential risks and benefits. The principal arguments against testing asymptomatic individuals younger than age 18 years are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have educational and career implications. However, early detection of familial HCM may provide helpful insight to guide management of minors, particularly in the setting of known early-onset and/or aggressive disease. A positive molecular genetic test may guide more stringent clinical screening for the onset of asymptomatic but clinically detectable HCM and earlier risk assessment for sudden death. The latter is an important consideration for young people participating in competitive sports. Currently, there is no evidence to indicate that physical activity should be strictly restricted in individuals who have a mutation in one of the genes encoding different components of the sarcomere, but no clinical evidence of HCM (i.e., no LVH); however, parents may wish to encourage development of interests other than serious competitive athletics. Furthermore, a negative test result in the context of known mutation in the family can provide reassurance that the person is not at risk of developing HCM and thus obviate unnecessary screening.
Clinical testing is always indicated in symptomatic individuals regardless of age. Individuals who are symptomatic during childhood usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents (see Genetic Testing; pdf).
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for familial HCM is possible by analyzing fetal DNA extracted from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation for disease-causing mutations. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Risk assessment for SCD is essential to management of individuals diagnosed with familial hypertrophic cardiomyopathy (HCM).
The clinical parameters analyzed to assess an individual’s risk for SCD include the following:
Personal history of aborted/resuscitated sudden death or cardiac arrest
Family history of SCD
Extreme LVH (>30mm)
Hypotensive blood pressure response to exercise
Significant ventricular ectopy on Holter monitoring
Unexplained syncope
In addition to a detailed personal medical and family history, a thorough risk assessment should include the following:
Echocardiogram to measure the degree of LVH
Exercise testing to assess blood pressure response to exercise
Holter monitoring for significant ventricular ectopy
Accurate risk assessment is difficult because the positive and negative predictive value of any single parameter is low. However, the presence of two or more risk factors has been associated with an increased risk for sudden cardiac death [Elliott et al 2000] and, conversely, the absence of any risk features places an individual in a low-risk category. However, controversy remains as to the appropriate interpretation of risk factors and risk stratification for an individual requires detailed and thoughtful evaluation.
Note: (1) All individuals who have survived prior cardiac arrest or had resuscitated sudden death should have an implantable cardioverter-defibrillatory (ICD) implanted for secondary prevention. (2) Individuals without prior events who are deemed to be at increased risk based on the above criteria should also be considered for ICD implantation for primary prevention of SCD.
No treatments to prevent or decrease disease development or to reverse established manifestations currently exist.
Medical management used for symptom palliation typically relies on the following:
Beta blockers
Calcium channel blockers
Antiarrhythmics
Disopyramide (its negative inotropic effects can reduce obstructive physiology)
Diastolic dysfunction is a common feature of familial HCM that may contribute significantly to symptoms of exertional dyspnea and volume overload, independent of obstruction. Diastolic dysfunction is typically challenging to treat:
β-blockers and calcium channel blockers can be used to slow heart rate and increase diastolic filling time.
Diuretics may be considered judiciously to relieve symptomatic volume overload with the caveat that patients may be preload-dependent to maintain adequate cardiac output, particularly if obstructive physiology is present.
When symptomatic obstruction is refractory to medical therapy, either of the following may be considered to alleviate symptoms:
Ethanol septal ablation is a recently developed catheter-based procedure in which ethanol is injected through a septal perforator vessel in the IVS muscle bed to induce focal myocardial infarction targeting the thickest portion of the proximal septum, which is primarily responsible for obstructive physiology.
Surgical myectomy (removal of a section of muscle from the IVS) can reduce or eliminate symptoms and can potentially increase longevity.
For atrial fibrillation the goal is to restore and maintain sinus rhythm. Anticoagulation is also required because of the high risk for thromboembolic complications. Treatment options:
Beta blockers or calcium channel blockers
Antiarrhythmic drug therapy
Cardioversion
Catheter-based ablation
For the small subset of individuals who progress to heart failure, appropriate medical treatment for heart failure is necessary, including consideration for cardiac transplantation in some cases.
For individuals with familial HCM felt to be at increased risk for SCD, consideration of ICDs is warranted. ICDs are currently the best option for the prevention of SCD. Maron et al [2000b] reported an appropriate discharge rate of 7% per year in an entire cohort with ICDs, with an 11% and 5% per year appropriate discharge rate in persons who received ICDs for secondary prevention (after resuscitated sudden death or sustained ventricular tachycardia) and primary prevention, respectively.
Elliott et al [2006] found an appropriate ICD discharge rate in 15.4% (8/52) of their cohort who received ICD for primary (n=41) and secondary (n=11) prevention.
Patients with familial HCM who develop atrial fibrillation are at an increased risk for thromboembolic complications. For patients with persistent or paroxysmal atrial fibrillation, anticoagulation should be considered.
The hemodynamic changes associated with pregnancy and delivery place women with familial HCM at increased risk for obstetric complications, particularly if significant obstructive physiology is present. Experienced cardiovascular and high-risk obstetrics care is required.
Patients with obstructive physiology have traditionally been considered at moderate risk for infective endocarditis and previous guidelines have recommended antibiotic prophylaxis for this subgroup. Official guidelines were recently revised and decision making should be considered on an individual basis [Wilson et al 2007].
Risk for SCD should be reassessed approximately annually (or sooner if any clinical parameters change) to assess for changes in the risk profile [Maron et al 2003b].
Physical activity guidelines have been established to detail reasonable exercise restrictions for people with familial HCM:
Patients are instructed to avoid competitive endurance training and to use moderation in all physical activities.
Patients should avoid burst activities, like sprinting, as well as intense isometric exercise, such as heavy weight lifting [Maron et al 2004a].
To avoid exacerbation of obstructive physiology and worsening of symptoms, patients with outflow tract obstruction should be particularly careful to avoid the following:
Dehydration
Hypovolemia (therefore, diuretics must be used with caution)
Medications that decrease afterload (e.g., ACE inhibitors; angiotensin receptor blockers and other direct vasodilators; medications for erectile dysfunction, e.g., sildenafil)
Screening guidelines have been proposed for the longitudinal evaluation of
| Age | Screening Guideline |
|---|---|
| <12 years | Optional but recommended, particularly if any of the following are present: Family history of early HCM-related death, early development of LVH, or other adverse complications Competitive athlete in intense training program Symptoms Other clinical findings that suggest early LVH |
| 12-18 years | Repeat evaluation every 12-18 months |
| >18-21 years | Repeat evaluation approximately every 3-5 years or in response to any change in symptoms Tailor evaluation if the family has late-onset LVH or HCM-related complications |
[Adapted from Maron et al 2004b]
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Brigham and Women’s Hospital Cardiovascular Genetics Center
Web: www.brighamandwomens.org/cvcenter/genetics
26 May 2009 (cd) Revision: sequence analysis and prenatal testing available clinically for TNNC1-related familial hypertrophic cardiomyopathy.
5 August 2008 (me) Review posted live
11 June 2007 (ac) Original submission
