2.1. Brugada syndrome

More than 400 mutations in the SCN5A gene have been identified in people with Brugada syndrome, which is a heart condition characterized by an irregular heart rhythm (arrhythmia). SCN5A gene mutations also cause sudden unexpected nocturnal death syndrome (SUNDS), which was originally described in Southeast Asian populations. Researchers have since determined that SUNDS and Brugada syndrome are the same disorder.

Some SCN5A gene mutations associated with Brugada syndrome change single protein building blocks (amino acids) in the SCN5A protein. These mutations alter the structure of ion channels made with the SCN5A protein and disrupt the flow of sodium ions into cardiac muscle cells. Other mutations prevent the SCN5A gene from producing any functional ion channels, which also reduces the inward flow of sodium ions. A disruption in ion transport changes the way the heart beats, leading to the arrhythmia often found in Brugada syndrome and SUNDS.

2.2. Progressive familial heart block

A few mutations in the SCN5A gene have been found to cause progressive familial heart block. This condition alters the normal beating of the heart and can lead to fainting (syncope) or sudden cardiac arrest and death. The SCN5A gene mutations change single amino acids in the SCN5A protein. Channels made with this altered protein allow little or no sodium to enter the cell. Cardiac cells with these altered channels have difficulty producing and transmitting electrical signals that coordinate normal heartbeats. Interruption of this signaling is known as heart block. The impaired cardiac cells die, leading to a buildup of scar tissue (fibrosis) over time that worsens the heart block.

2.3. Romano-Ward syndrome

At least 238 mutations in the SCN5A gene are known to cause Romano-Ward syndrome, which is the most common form of an arrhythmia called long QT syndrome. Mutations in this gene account for five to 10 percent of cases of Romano-Ward syndrome. In individuals with this condition the cardiac muscle takes longer than usual to recharge between beats.

The SCN5A gene mutations that cause Romano-Ward syndrome include changes in single amino acids and deletions or insertions of a small number of amino acids in the SCN5A protein. Channels made with these altered SCN5A proteins stay open longer than usual, which allows sodium ions to continue flowing into cardiac muscle cells abnormally. This delay in channel closure alters the transmission of electrical signals in the heart, increasing the risk of an irregular heartbeat that can cause syncope or sudden death.

2.4. Sick sinus syndrome

At least 16 mutations in the SCN5A gene have been found to cause another heart condition called sick sinus syndrome. This condition affects the function of the sino-atrial (SA) node, which is an area of specialized cells in the heart that functions as a natural pacemaker. The SCN5A gene mutations that cause sick sinus syndrome lead to the production of nonfunctional sodium channels or abnormal channels that cannot transport ions properly. The flow of these ions is essential for creating the electrical impulses that start each heartbeat and spread these signals to other areas of the heart. Mutations reduce the flow of sodium ions, which alters the SA node's ability to create and spread electrical signals. These changes increase the risk of abnormally fast or slow heartbeats, which can cause dizziness, light-headedness, syncope, and related symptoms.

2.5. Other disorders

Variations in the SCN5A gene are associated with several other heart conditions. These include potentially life-threatening forms of arrhythmia called atrial fibrillation and ventricular fibrillation. The genetic variations associated with these conditions alter the flow of sodium ions through the channel, which can lead to abnormal heart rhythms and affect the heart's ability to pump blood.

SCN5A gene mutations have also been identified in some cases of sudden infant death syndrome (SIDS). SIDS is a major cause of death in babies younger than 1 year. It is characterized by sudden and unexplained death, usually during sleep. Researchers are working to determine how changes in the SCN5A gene could contribute to SIDS. Other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of this disorder.

Certain drugs, including medications used to treat arrhythmias, infections, seizures, and psychotic disorders, can lead to an abnormal heart rhythm in some people. This drug-induced heart condition, which is known as acquired long QT syndrome, increases the risk of cardiac arrest and sudden death. A small percentage of cases of acquired long QT syndrome occur in people who have an underlying change in the SCN5A gene.