CACNA1C

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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.

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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.