Hypertrophic cardiomyopathy

The clinical features of hypertrophic cardiomyopathy (HCM), including symptoms and morphologic or functional anomalies, are heterogenous. Symptoms are often variable, and may be entirely absent. A patient with HCM may have:

• chest pain;
• dyspnoea;
• palpitations and light-headedness; and/or
• episodes of syncope, which should be regarded as a possible indicator of elevated prognostic risk and should be escalated appropriately.

When examining a patient with suspected HCM, it is important to assess them for a systolic murmur by auscultation during a Valsalva manoeuvre, or while asking them to stand from a squat.

A detailed multi-generational family history should be obtained, noting any major cardiovascular events and unexplained premature deaths, and identifying family members at risk.

Diagnostic criteria for HCM are covered in detail in the following resources:

• Adult with hypertrophic cardiomyopathy;
• Child with hypertrophic cardiomyopathy; and
• Infant with hypertrophic cardiomyopathy.

Variants in sarcomeric protein genes

• In terms of aetiology, HCM is most commonly caused by sarcomeric gene variants. These genes encode proteins of the cardiac myocyte’s contractile apparatus.
• Another common cause is variants in genes encoding myofilament proteins of the cardiac sarcomere and its related structures (of which there are 1,500 currently documented).
• HCM is usually inherited in an autosomal dominant pattern with variable expressivity and age-related penetrance.
• The possibility of incomplete penetrance and variable age-related penetrance are important to consider when conducting clinical screening: individuals with a pathogenic genetic variant who have not developed HCM at the time of testing may develop the disease later in life, and can still pass on the genetic cause to their children. For example, nearly half of adults under the age of 50 with an MYBPC3 likely pathogenic or pathogenic variant do not have cardiac hypertrophy. In this way, HCM can sometimes appear to skip a generation.

Table 1 provides a detailed list of sarcomeric and non-sarcomeric genes that have been associated with HCM.

Table 1: Genes in which variants have been associated with hypertrophic cardiomyopathy

Non-sarcomeric causes of left ventricular hypertrophy

• There are a range of clinical phenotypes in which the nature and extent of left ventricular hypertrophy (LVH) mimics that of HCM arising from sarcomeric variants. These diseases are often described as ‘phenocopies’ of HCM and, while they are rare, it is important to differentiate between sarcomeric HCM and phenocopies because the natural history, prognosis and, in some instances, management are markedly different. Genomic testing, alongside other clinical tests, can be performed to determine whether a causative variant for a phenocopy disease is present.

Transthyretin (ATTR) amyloidosis

• ATTR amyloidosis arises from the misfolding and deposition of the transthyretin protein.
• ATTR amyloidosis can be subdivided into its wild-type and hereditary forms. Hereditary ATTR amyloidosis is caused by TTR gene variants. The transmission of hereditary ATTR amyloidosis is autosomal dominant with variable penetrance. ATTR amyloidosis is an important differential diagnosis in older patients presenting with unexplained LVH, particularly those with symptoms of heart failure with preserved ejection fraction and/or aortic stenosis.

Fabry disease and alpha-galactosidase A gene

• Fabry disease is an X-linked recessive glycolipid storage condition resulting from variants in the gene encoding alpha-galactosidase A (GLA). The cardiac manifestations of Fabry disease are morphologically similar to HCM. In women, it is an important differential diagnosis in cases of late-onset LVH with no concomitant hypertension or aortic stenosis.

Noonan syndrome and RAS MAPK pathway genes

• About 20% of individuals with Noonan syndrome will also develop LVH.

PRKAG2 and LAMP2 genes

• PRKAG2 is an enzyme that regulates glucose uptake and glycolysis. Variants in the PRKAG2 gene, which are inherited in an autosomal dominant pattern, can be associated with a HCM phenotype often accompanied by conduction disease and/or pre-excitation.
• Variants in LAMP2 cause X-linked Danon disease, also known as glycogen storage disease IIb. It is characterised by LVH, skeletal myopathy and a variable degree of intellectual disability. Impaired systolic function is often present.

• HCM is most often an autosomal dominant condition. This means that an affected individual has a 50% chance of passing the dominant allele to each of their children.
• Diagnostic genomic testing should be performed in probands who meet diagnostic criteria for HCM, and who have relatives who will benefit from cascade testing following a genomic diagnosis (this is predictive genomic testing). Diagnostic genomic testing should also be considered if a diagnosis will alter the management plan – for example, if there is suspicion of an HCM phenocopy condition.
• The main indication for genomic testing in HCM is to facilitate pre-symptomatic and/or pre-phenotypic diagnoses in family members following a diagnosis of HCM in a family member. This is important because HCM is a relatively common disease, is often asymptomatic, and even affected individuals without symptoms can be at elevated prognostic risk.
• As many as 50% of individuals with a clinical diagnosis of HCM will not have a genetic cause identified. These individuals may be older, and more likely to have comorbidities such as hypertension and diabetes, which may contribute to the development of the hypertrophy. In others, the ‘negative’ test result could represent an equivocal or false negative result. The failure to identify a genetic cause of HCM in a proband does not prove that their disease is not genetically determined. Following a non-diagnostic genomic test in a proband, clinical screening of family members is recommended.

Clinical management of individuals diagnosed with HCM often requires a multidisciplinary approach, and should be performed in conjunction with a specialist inherited cardiac conditions service. A comprehensive approach to HCM management will address the following.

• Confirmation of the diagnosis of HCM, including evaluation for phenocopies and unusual forms of the condition. Genomic testing is not usually required for a diagnosis of HCM, but should be considered when unusual forms, including metabolic and syndromic forms of LVH, are suspected.
• Assessment of symptom status, including the identification of the pathophysiological mechanisms most likely to be responsible for symptoms, and indications for symptomatic therapies. Symptomatic management most often addresses left ventricular outflow obstruction, but symptoms may also be the result of diastolic dysfunction, systolic impairment, myocardial ischaemia, arrhythmias and other mechanisms.
• Assessment of prognostic risks, including from sudden arrhythmic death, thrombo-embolic disease and progressive heart failure. Implantable defibrillators, anticoagulation and heart failure therapies (device, pharmacological and transplant) may be indicated to mitigate risks.
• An individualised evaluation that considers implications that HCM and its treatment may have for the patient’s lifestyle (in areas such as competitive and/or endurance sports and recreational drug-taking), life events (for example, pregnancy, anaesthesia and comorbidities) and livelihood (for example, for professional athletes and for licensing regulations in public transportation).
• Addressing implications for family members of an individual with a genetically determined condition. A genomic diagnosis greatly facilitates the accuracy, efficiency and cost-effectiveness of cascade family screening, which is the principal reason to consider testing in a proband with HCM.

For clinicians

• NHS England: National Genomic Test Directory

For patients

• British Heart Foundation: Hypertrophic cardiomyopathy
• British Heart Foundation: Life with hypertrophic cardiomyopathy
• Cardiomyopathy UK: HCM online support group
• Cardiomyopathy UK: Hypertrophic cardiomyopathy
• NHS Health A to Z: Cardiomyopathy