Arrhythmia is any change from the normal sequence of electrical impulses
of the heart. These impulses may happen too fast (tachycardia), too
slowly (bradycardia), or erratically. Types of arrhythmias include
atrial fibrillation, conduction disorders, premature contraction,
ventricular fibrillation, tachycardia, and bradycardia. Arrhythmias can
present with a broad spectrum of symptoms including palpitation, a
fluttering sensation, fatigue, dizziness, lightheadedness, syncope,
rapid heartbeat, shortness of breath, chest pain, and sudden cardiac
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal
dominant condition characterized by abnormalities in cardiac structure
and rhythm. The fibrofatty replacement of myocardium can predispose
affected individuals to ventricular tachycardia and sudden death in
young individuals and athletes. Common presenting features include
heart palpitation, syncope, and death. Other diagnostic criteria
include right ventricular dilation and reduction of right ventricular
function, and right ventricular aneurysms. The phenotype of ARVD/C is
highly variable and while it primarily affects the right ventricle, it
may involve the left ventricle as well.
Brugada syndrome is characterized by cardiac conduction abnormalities.
These cardiac abnormalities can result in sudden death. Often features
such as syncope and/or arrhythmias present in adulthood; however, the
age of diagnosis ranges from two days to 85 years. Pathogenic variants
in eight genes are known to cause Brugada syndrome. Only 25% of
individuals with Brugada syndrome have an identifiable pathogenic
variant in one of the eight genes known to cause it. Most individuals
with Brugada syndrome have an affected parent but approximately 1% of
cases are the result of a de novo pathogenic variant
Catecholaminergic Polymorphic Ventricular Tachycardia
polymorphic ventricular tachycardia (CPVT) is characterized by cardiac
electrical instability. This instability can be exacerbated by acute
activation of the adrenergic nervous system, such as during exercise or
extreme emotional events. These episodes have an underlying cause of
ventricular tachycardia, which may progress into ventricular
Hereditary dilated cardiomyopathy (DCM) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, depending on the gene involved. DCM is characterized by left ventricular enlargement and reduced myocardial contraction force. Typically, DCM presents with one of three features: heart failure, thromboembolic disease, or arrhythmias and/or conduction system disease. Approximately 20-50% of idiopathic dilated cardiomyopathy (those cases not due to acquired causes) are thought to have a genetic cause.Hypertrophic Cardiomyopathy
Hereditary hypertrophic cardiomyopathy (HCM) is inherited in an autosomal dominant manner. HCM is characterized by left ventricular hypertrophy in the absence of a predisposing cardiac or cardiovascular condition. The manifestation of HCM is extremely variable, even within the same family, and can range from asymptomatic to progressive heart failure. Other features include syncope, presyncope, shortness of breath, chest pain, orthostasis, and palpitations. The onset of HCM is usually during adolescence or young adulthood; however, it can range from infancy to much later in adult life. The prevalence of HCM is approximately 1 in 500 and ~55-70% of cases are caused by a mutation in one of the genes that encode a part of the sarcomere.Left Ventricular Noncompaction
Familial left ventricular noncompaction (LVNC) is an autosomal dominant or X-linked cardiomyopathy. The distinct diagnostic features of LVNC (a thick, bilayered myocardium, deep intertrabecular recesses, and prominent ventricular trabeculations) are secondary to an arrest of myocardial maturation during embryo development. Individuals with LVNC may be symptomatic or asymptomatic. Major complications of LVNC include heart failure, thromboembolic events, arrhythmias, and sudden cardiac death. Diagnosis can occur prenatally through late adulthood. The manifestation of LVNC is extremely variable, even within the same family. Approximately 30% of isolated LVNC are caused by a mutation in a sarcomere gene. Long QT Syndrome
Long QT syndrome (LQTS) is characterized by a QT interval that is
prolonged on the surface electrocardiogram and a predisposition to early
after depolarizations and torsades de pointes. LQTS can present
clinically with palpitations, presyncope, syncope, or sudden cardiac
death. Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders
Thoracic aortic aneurysm and dissection (TAAD) has a highly variable
presentation and age of onset. It is characterized by dilation and
dissections of the ascending thoracic aorta and/or ascending aorta. An
aneurysm involving the descending thoracic aorta is observed rarely.
Without surgical repair of the ascending aorta, individuals with TAAD
have continual enlargement of the ascending aorta that leads to an acute
aortic dissection. Isolated TAAD is typically inherited in an autosomal
dominant manner with variable expression and reduced penetrance. Only
about 20% of familial non-syndromic TAAD is attributed to pathogenic
variants in known genes.
TAAD can also be present as part of a
genetic syndrome. Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos
syndrome vascular type, multisystemic smooth muscle dysfunction
syndrome, and congenital contracturalarachnodactyly all have TAAD as
part of their clinical spectrum.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is increased pulmonary artery
pressure in the absence of common causes of pulmonary hypertension, such
as lung, heart, or thromboembolic chronic diseases. It is thought that
both genetic and environmental factors that alter vascular structure and
function contribute to the pathogenesis of PAH.
cases of PAH are usually inherited in an autosomal dominant manner. With
the identification of pathogenic variants in genes known to cause PAH,
what was previously thought to be idiopathic PAH is now known to be
genetic. A pathogenic variant in the BMPR2
gene causes ~70% of hereditary cases of PAH and in 10-40% of idiopathic PAH. Pathogenic variants in the CAV1
gene cause PAH.
Heterozygous pathogenic variants in the ENG
(previously known as ALK1
genes cause hereditary hemorrhagic telangiectasia (HHT). HHT is an
autosomal dominant vascular disorder characterized by acquired cutaneous
telangiectasias and arteriovenous malformations that can lead to the
development of PAH.
Restrictive cardiomyopathy (RCM) is a primary myocardial disorder in which the main feature, restrictive ventricular physiology, develops early in the disease. RCM is characterized by inadequate ventricular relaxation during diastole. Onset can range from childhood to late adult hood. Major complications of RCM can include congestive heart failure, cerebrovascular accidents, and arrhythmias. Cardiac restriction may occur secondary to many genetic syndromes, such as Pompe disease and Fabry disease. Short QT Syndrome
Short QT syndrome (SQTS) is characterized by an
abnormally short QT interval and susceptibility to both ventricular
tachyarrhythmias and atrial fibrillation.Sudden Cardiac Arrest
Sudden cardiac arrest is the abrupt loss of heart function due to a
malfunction in the heart's electrical system, such as an arrhythmia.
The individual may or may not have been diagnosed with heart disease.
- American Heart Assocation.
- Ma and Chung. (2014). Hum Genet. [Epub ahead of print]
- Paterick et al., (2012), J Am Soc Echocardiog, 25:363-375.
- Peters and Khandheria, (2012), Curr Cardiol Rep, 14:381-388.
- Sen-Chowdhry et al., (2010), Heart Failure Clin, 6:179-186.