Timothy syndrome is a rare disorder that primarily affects the heart but can affect many other areas of the body. The severity of this condition varies among affected individuals, although it is often life-threatening.

Timothy syndrome is characterized by a heart condition called long QT syndrome, which causes the heart (cardiac) muscle to take longer than usual to recharge between beats. This abnormality in the heart's electrical system can cause severe abnormalities of the heart rhythm (arrhythmias), which can lead to sudden death. Some people with Timothy syndrome are also born with structural heart defects (cardiomyopathy) that affect the heart's ability to pump blood effectively.

As a result of these serious heart problems, some people with Timothy syndrome live only into childhood. In about 80 percent of cases of Timothy syndrome, the cause of death is a severe form of arrhythmia called ventricular tachycardia, in which the lower chambers of the heart (the ventricles) beat abnormally fast, often leading to cardiac arrest (the heart suddenly stops beating) and sudden death.

Timothy syndrome is also characterized by webbing or fusion of the skin between some fingers or toes (cutaneous syndactyly). About half of affected people have distinctive facial features such as a flattened nasal bridge, low-set ears, a small upper jaw, and a thin upper lip. Children with this condition have small, misplaced teeth and frequent cavities (dental caries). Additional signs and symptoms of Timothy syndrome can include baldness at birth, low muscle tone (hypotonia), frequent infections, episodes of low blood glucose (hypoglycemia), and an abnormally low body temperature (hypothermia). The respiratory system and gastrointestinal tract can also be affected.

Neuropsychiatric features are also common in individuals with Timothy syndrome. Researchers have found that many children with Timothy syndrome have the characteristic features of autism spectrum disorders. Affected children tend to have impaired communication and socialization skills, as well as delayed development of speech and language. Poor coordination is also frequent in affected individuals. Other nervous system disorders that can occur in Timothy syndrome include attention-deficit/hyperactivity disorder, intellectual disability and recurrent seizures (epilepsy); some affected individuals have photosensitive epilepsy, in which seizures are triggered by flashing lights.

Variants (also known as mutations) in the CACNA1C gene cause Timothy syndrome. This gene provides instructions for making a protein that acts as a small hole or pore (a channel) across cell membranes. This channel, known as CaV1.2, transports positively charged calcium atoms (calcium ions) into cardiac cells (cardiomyocytes) and nerve cells (neurons) in the brain. Calcium ions are important for many cellular functions, including regulating the electrical activity of cells, cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes, particularly those involved in the development of the brain and bones before birth.

Variants in the CACNA1C gene that cause Timothy syndrome change the structure of CaV1.2 channels. These gene changes lead to altered channels that stay open much longer than usual, which allows calcium ions to continue flowing into cells abnormally. The resulting overload of calcium ions within cardiac muscle cells changes the way the heart beats and can cause abnormal heart muscle contractions and arrhythmia. It is thought that the altered channels and flow of calcium ions also impair regulation of certain genes, resulting in the facial, dental, and neurological abnormalities in Timothy syndrome.

Other variants in the CACNA1C gene can cause isolated features of Timothy syndrome without the other associated health problems of the condition. For example, some people with CACNA1C gene variants may have only long QT syndrome or only neurodevelopmental disorders.

Normal Function

The CACNA1C gene provides instructions for making one of several calcium channels. Calcium channels, which transport positively charged calcium atoms (calcium ions) into cells, play a key role in a cell's ability to generate electrical signals. Calcium ions are important for many cellular functions, including regulating the electrical activity of cells, cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes, particularly those involved in the development of the brain and bones before birth.

The calcium channel produced from the CACNA1C gene is known as CaV1.2. These channels are found in many types of cells, although they appear to be particularly important for the function of heart cells (cardiomyocytes) and nerve cells (neurons) in the brain. In the heart, CaV1.2 channels open and close at specific times to control the flow of calcium ions into cardiomyocytes at each heartbeat. How long the channels are open and closed is regulated to maintain normal heart function. In the brain, CaV1.2 channels are thought to be involved in memory, the fear response, and the rapid transmission of nerve signals; however, the role of these channels in the brain and other tissues is not completely understood.

Researchers have discovered that many different versions (isoforms) of the CaV1.2 channel can be produced from the CACNA1C gene by a mechanism called alternative splicing. This mechanism produces different versions of the channel by cutting and rearranging the genetic instructions in different ways. Some versions of the CaV1.2 channel are more common than others in certain parts of the body. For example, in the heart and brain, about 80 percent of CaV1.2 channels are made with a particular segment known as exon 8. The other 20 percent of CaV1.2 channels contain a slightly different version of this segment, known as exon 8A. This difference becomes important when researchers are studying the effects of CACNA1C mutations in various tissues.

Health Conditions Related to Genetic Changes

Short QT syndrome

MedlinePlus Genetics provides information about Short QT syndrome

Timothy syndrome

Variants (also known as mutations) in the CACNA1C gene have been found to cause Timothy syndrome. This condition primarily affects the heart but can affect many other areas of the body, including the fingers and toes, teeth, nervous system, and immune system. Timothy syndrome is characterized by a heart condition called long QT syndrome, which causes the heart (cardiac) muscle to take longer than usual to recharge between beats. This abnormality in the heart's electrical system can cause severe abnormalities of the heart rhythm (arrhythmias), which can lead to sudden death.

Variants in the CACNA1C gene change the structure of CaV1.2 channels throughout the body. The altered channels stay open much longer than usual, which allows calcium ions to continue flowing into cells abnormally. The resulting overload of calcium ions within cardiac muscle cells changes the way the heart beats and can cause abnormal heart muscle contraction and arrhythmia. It is thought that the altered channels and calcium ion flow also impair regulation of certain genes during development, resulting in the facial, dental, and neurological abnormalities in Timothy syndrome.

In some cases, people with CACNA1C gene variants have long QT syndrome without the other features of Timothy syndrome. It is unclear why some people have only heart problems while other have additional features.

Brugada syndrome

MedlinePlus Genetics provides information about Brugada syndrome

Other disorders

Variants in the CACNA1C gene have also been identified in people with a condition called long QT syndrome 8. These individuals have arrhythmia that can lead to fainting (syncope) or cardiac arrest and sudden death without the other features of Timothy syndrome (described above). Research suggests that CACNA1C gene variants that cause long QT syndrome 8 occur in a different part of the gene than those that cause Timothy syndrome. While these CACNA1C gene variants alter CaV1.2 channels and calcium channel flow, it is unclear why they cause only heart problems.

Other variants in the CACNA1C gene have been found in individuals with a condition known as CACNA1C-related disorder. People with this condition have some but not all of the features of Timothy syndrome. These features can include seizures, intellectual disability, autism spectrum disorder, anxiety, and walking difficulty. Individuals with this condition can also experience delayed speech, language or motor skills. Some affected individuals have heart problems separate from long QT syndrome. The severity of CACNA1C-related disorder varies greatly; some people with the condition are mildly affected with only a few features whereas others have many features and are severely affected.

Other Names for This Gene

• CAC1C_HUMAN
• CACH2
• CACN2
• CACNL1A1
• calcium channel, cardic dihydropyridine-sensitive, alpha-1 subunit
• calcium channel, L type, alpha 1 polypeptide, isoform 1, cardic muscle
• calcium channel, voltage-dependent, L type, alpha 1C subunit
• CaV1.2
• CCHL1A1
• DHPR, alpha-1 subunit
• MGC120730
• voltage-dependent L-type calcium channel alpha 1C subunit
• voltage-gated calcium channel alpha subunit Cav1.2

Genomic Location

This condition is considered to have an autosomal dominant pattern of inheritance, which means one copy of the altered CACNA1C gene in each cell is sufficient to cause the disorder. Most cases result from new (de novo) variants in the gene. In these cases, there is no history of the disorder in their family.

Because of the severity of Timothy syndrome, it is rare for an affected individual to be able to pass on the disease-causing variant. Although rare, some people with Timothy syndrome inherit the altered gene from an unaffected parent who is mosaic for a CACNA1C gene variant. Mosaicism means that the parent has the variant in some cells (including egg or sperm cells), but not in others.

Timothy syndrome is a rare condition; fewer than 100 people with this disorder have been reported worldwide.