Progressive familial heart block is a genetic condition that alters the normal beating of the heart. A normal heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. These signals begin in a specialized cluster of cells called the sinoatrial node (the heart's natural pacemaker) located in the heart's upper chambers (the atria). From there, a group of cells called the atrioventricular node carries the electrical signals to another cluster of cells called the bundle of His. This bundle separates into multiple thin spindles called bundle branches, which carry electrical signals into the heart's lower chambers (the ventricles). Electrical impulses move from the sinoatrial node down to the bundle branches, stimulating a normal heartbeat in which the ventricles contract slightly later than the atria.

Heart block occurs when the electrical signaling is obstructed anywhere from the atria to the ventricles. In people with progressive familial heart block, the condition worsens over time: early in the disorder, the electrical signals are partially blocked, but the block eventually becomes complete, preventing any signals from passing through the heart. Partial heart block causes a slow or irregular heartbeat (bradycardia or arrhythmia, respectively), and can lead to the buildup of scar tissue (fibrosis) in the cells that carry electrical impulses. Fibrosis contributes to the development of complete heart block, resulting in uncoordinated electrical signaling between the atria and the ventricles and inefficient pumping of blood in the heart. Complete heart block can cause a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, fainting (syncope), or sudden cardiac arrest and death.

Progressive familial heart block can be divided into type I and type II, with type I being further divided into types IA and IB. These types differ in where in the heart signaling is interrupted and the genetic cause. In types IA and IB, the heart block originates in the bundle branch, and in type II, the heart block originates in the atrioventricular node. The different types of progressive familial heart block have similar signs and symptoms.

Most cases of heart block are not genetic and are not considered progressive familial heart block. The most common cause of heart block is fibrosis of the heart, which occurs as a normal process of aging. Other causes of heart block can include the use of certain medications or an infection of the heart tissue.

Mutations in the SCN5A and TRPM4 genes cause most cases of progressive familial heart block types IA and IB, respectively. The proteins produced from these genes are channels that allow positively charged atoms (cations) into and out of cells. Both channels are abundant in heart (cardiac) cells and play key roles in these cells' ability to generate and transmit electrical signals. These channels play a major role in signaling the start of each heartbeat, coordinating the contractions of the atria and ventricles, and maintaining a normal heart rhythm.

The SCN5A and TRPM4 gene mutations that cause progressive familial heart block alter the normal function of the channels. As a result of these channel alterations, cardiac cells have difficulty producing and transmitting the electrical signals that are necessary to coordinate normal heartbeats, leading to heart block. Death of these impaired cardiac cells over time can lead to fibrosis, worsening the heart block.

Mutations in other genes, some of which are unknown, account for the remaining cases of progressive familial heart block.

Normal Function

The SCN5A gene belongs to a family of genes that provide instructions for making sodium channels. These channels open and close at specific times to control the flow of positively charged sodium atoms (sodium ions) into cells. The sodium channels containing proteins produced from the SCN5A gene are abundant in heart (cardiac) muscle cells and play key roles in these cells' ability to generate and transmit electrical signals. These channels play a major role in signaling the start of each heartbeat, coordinating the contractions of the upper and lower chambers of the heart, and maintaining a normal heart rhythm.

Health Conditions Related to Genetic Changes

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.

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.

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.

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.

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Familial dilated cardiomyopathy

MedlinePlus Genetics provides information about Familial dilated cardiomyopathy

Left ventricular noncompaction

MedlinePlus Genetics provides information about Left ventricular noncompaction

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.

Other Names for This Gene

• HH1
• LQT3
• Nav1.5
• SCN5A_HUMAN
• Sodium channel protein, cardiac muscle alpha-subunit
• sodium channel, voltage gated, type V alpha subunit
• sodium channel, voltage-gated, type V, alpha (long QT syndrome 3)
• sodium channel, voltage-gated, type V, alpha subunit
• SSS1

Genomic Location

Normal Function

The TRPM4 gene provides instructions for making a protein called transient receptor potential cation channel subfamily M member 4 (TRPM4). This protein acts as a channel, opening and closing at specific times to control the flow of positively charged atoms (cations) into and out of cells. The TRPM4 channel is embedded in the outer membrane of cells throughout the body, but it is abundant in heart (cardiac) cells and plays key roles in these cells' ability to generate and transmit electrical signals. TRPM4 channels play a major role in signaling the start of each heartbeat, coordinating the contractions of the upper and lower chambers of the heart, and maintaining a normal heart rhythm.

In addition to regulating electric signaling in the heart, the TRPM4 channel is important for the normal functioning of the immune system, the nervous system, the kidneys, and the pancreas.

Health Conditions Related to Genetic Changes

Progressive familial heart block

A few mutations in the TRPM4 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 TRPM4 gene mutations change single protein building blocks (amino acids) in the TRPM4 channel. The altered channels have increased activity at the cell membrane, which likely alters the cell's ability to generate electrical signals because of the increased cation flow. Cardiac cells with these altered channels have difficulty producing and transmitting electrical signals that coordinate normal heartbeats. Interruption of this signaling causes heart block. Death of these impaired cardiac cells over time can lead to a buildup of scar tissue (fibrosis), worsening the heart block.

Brugada syndrome

MedlinePlus Genetics provides information about Brugada syndrome

Other Names for This Gene

• calcium-activated non-selective cation channel 1
• hTRPM4
• long transient receptor potential channel 4
• LTrpC4
• melastatin-4
• transient receptor potential cation channel, subfamily M, member 4
• TRPM4_HUMAN
• TRPM4B

Genomic Location

Progressive familial heart block types I and II are inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Some people with TRPM4 gene mutations never develop the condition, a situation known as reduced penetrance.

In most cases, an affected person has one parent with progressive familial heart block.

The prevalence of progressive familial heart block is unknown. In the United States, about 1 in 5,000 individuals have complete heart block from any cause; worldwide, about 1 in 2,500 individuals have complete heart block.