Long QT syndrome

Cardiology section

Long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on the electrocardiogram (ECG). The QT interval represents the time it takes for the heart to repolarize, or reset, after each

heartbeat. Prolongation of the QT interval can lead to a predisposition to a specific type of ventricular arrhythmia called Torsades de Pointes (TdP), which can result in syncope (fainting), seizures, or sudden cardiac arrest.

ABOUT LONG QT SYNDROM

UNDERSTANDING Long QT Syndrome

Long QT Syndrome (LQTS): Causes and Subtypes

Long QT Syndrome (LQTS) can be either inherited or acquired. Inherited LQTS is primarily caused by mutations in genes encoding cardiac ion channels, disrupting normal repolarization processes, leading to  QT prolongation and arrhythmias.

Acquired LQTS can result from certain medications, electrolyte imbalances, or other medical conditions. Several subtypes of LQTS are associated with mutations in different genes.

Mutations in at least 15 genes have been linked to LQTS. These genes encode ion channels or channel-associated proteins involved in cardiac repolarization. The most common genes associated with LQTS include:

KCNQ1 (Potassium Voltage-Gated Channel Subfamily Q Member 1):

Mutations in the KCNQ1 gene are associated with LQT1, the most common subtype of LQTS, accounting for approximately 35-45% of cases. KCNQ1 encodes the α-subunit of the slow delayed rectifier potassium channel (IKs), which plays a crucial role in cardiac repolarization.

KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member 2):

Mutations in the KCNH2 gene are associated with LQT2, accounting for approximately 30-40% of cases. KCNH2 encodes the α-subunit of the rapid delayed rectifier potassium channel (IKr), which is responsible for a significant portion of cardiac repolarization.

SCN5A (Sodium Voltage-Gated Channel Alpha Subunit 5):

Mutations in the SCN5A gene are associated with LQT3, accounting for approximately 5-10% of cases. SCN5A encodes the α-subunit of the cardiac sodium channel (Nav1.5), which is involved in the initial phase of cardiac depolarization.

KCNE1 (Potassium Voltage-Gated Channel Subfamily E Regulatory Subunit 1)

Mutations in the KCNE1 gene are associated with LQT5, a rare subtype of LQTS. KCNE1 encodes a β-subunit that modulates the activity of the IKs potassium channel.

KCNE2 (Potassium Voltage-Gated Channel Subfamily E Regulatory Subunit 2):

Mutations in the KCNE2 gene are associated with LQT6, another rare subtype of LQTS. KCNE2 also encodes a β-subunit that modulates potassium channel activity.

ANK2 (Ankyrin 2):

Mutations in the ANK2 gene have been associated with LQT4, a rare subtype of LQTS. ANK2 encodes ankyrin-B, which plays a role in membrane protein targeting and stabilization, including cardiac ion channels.

CACNA1C (Calcium Voltage-Gated Channel Subunit Alpha1 C):

Mutations in the CACNA1C gene have been associated with LQT8 (also known as Timothy syndrome), a rare multisystem disorder characterized by LQTS, syndactyly, facial dysmorphism, and other features. CACNA1C encodes the α-subunit of the L-type calcium channel (Cav1.2).

These genes play critical roles in cardiac repolarization and the regulation of the cardiac action potential.

Mutations in these genes disrupt normal ion channel function, leading to prolonged QT intervals on the electrocardiogram (ECG) and an increased risk of life-threatening arrhythmias such as Torsades de Pointes (TdP) and sudden cardiac death. Genetic testing can identify specific mutations associated with LQTS and guide risk assessment, management, and family screening for affected individuals and their relatives.