Introductory Overview

Hypertrophic cardiomyopathy (HCM, OMIM#192600) is a well-known primary disease of the myocardium. HCM is defined by unexplained ventricular hypertrophy with preferential hypertrophy of the septum and anterior left ventricular wall in the absence of a detectable cause.

This disorder has a prevalence within the general population of one in 500, or 0.2%. It follows a heterogeneous autosomal dominant inheritance pattern and often develops during childhood and adolescence. Individuals with the disease may develop myocardial ischemia, arrhythmia or heart failure. Notably, HCM is the most common cause of sudden cardiac death in young adults and athletes.

Genes encoding for cardiac sarcome proteins accounts for up to 60% of cases of HCM. The remaining causes include other genetic syndromes (mostly inherited metabolic and neuromuscular disorders) and non-genetic factors mimicking the genetic form of the disease [1].

Genes involved in HCM and corresponding estimated proportion of mutations causing HCM:

Prescription Guidance

Clinical Indication

This test is indicated for:

• Diagnosis confirmation and refinement of a patient with a definite or suspected cardiomyopathy
• Predictive diagnosis in asymptomatic relatives [1]

Patient Eligibility

• Individuals with a suspected or confirmed diagnosis of HCM
• Individuals with a family history of sudden death
• Individuals with left ventricular thickening and suspected HCM
• Athletes with ventricular hypertrophy
• Genetic study of family members for abnormalities identified in index cases

Test Benefits & Risk Management

Benefits of this test are:

• The diagnosis confirmation and refinement of a patient supposedly affected by HCM, e.g. discrimination between HCM and other causes of left ventricular (LV) hypertrophy, including hypertension, “athlete’s heart” and other metabolic or infiltrative storage disorders with LV hypertrophy that can mimic clinically diagnosed HCM (Fabry disease, Noonan disease, Danon disease, etc.).
  An early identification, would allow an earlier treatment of these different conditions.
• The subsequent identification of affected relatives in families where a causative HCM mutation has already been found. This would allow an earlier management of at-risk members and avoid unnecessary further screening of non-carriers.

Risk management includes, but is not limited to:

• Monitoring of the disease: Regular cardiologic evaluation is advised to detect clinical signs of HCM and to estimate the risk of sudden cardiac death [2].
• Lifestyle changes: Intense physical activity (e.g., burst activities, sprinting), or systematic isometric exercise (e.g., heavy lifting) will be discouraged [3].
• Implantable cardiac defibrillators (ICDs) for secondary or primary prevention in patients at right risk of sudden cardiac death [4].
• A range of drugs exists to manage specific symptoms. For instance, drugs appropriate to control heart failure symptoms, such as beta-blockers, which may be used to relieve palpitation and calcium antagonists, which can similarly reduce palpitations and chest pains [5].
• Surgical septal myectomy [6], which removes some of the thickened muscle from the septum thereby relieving obstruction or alcohol septal ablation [7] for progressive and drug-refractory heart failure caused by left ventricular outflow tract (LVOT) obstruction.
• Heart transplantation for systolic (or less frequently intractable diastolic) dysfunction associated with severe unrelenting symptoms [8].
• Drug therapy (Disopyramide, amiodarone, dronedarone) [2,5] or possibly radiofrequency ablation or surgical maze procedure for atrial fibrillation [9].

Test Characteristics

Panel Composition

This panel includes the 8 genes encoding for main cardiac sarcomere protein. It also comprises 3 genes responsible for most common HCM genocopies (HCM phenotype not due to mutations in sarcomeric genes), therefore also allowing for differential diagnosis.
It is estimated that > 80% of mutations currently reported for HCM are covered with this panel.

Technical Details

Methodology

• Targeted capture of all coding exons and exon-intron boundaries followed by NGS.
• Sanger sequencing on low coverage regions and all relevant variants

TAT

Two months on average