CACNA1C-Related Disorders (CRDs)

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Understanding CACNA1C-Related Disorders

CACNA1C-Related Disorders (CRDs) are caused by changes (variants) in the CACNA1C gene.

This gene makes the CaV1.2 calcium channel. That channel helps cells in the heart, brain and other organs talk to each other.

Different variants change the channel in different ways (increase, decrease, or mixed effects). Because CaV1.2 works in many tissues, CRDs can affect the heart, brain, metabolism, muscles and more. The exact combination of features varies greatly between people.

Why naming matters

Many names were used in the past (for example “cardiac-only Timothy” or “neurological CACNA1C disorder”). That caused confusion.

After an 18-month international consensus process finalised in 2025, experts and families agreed to one umbrella name: CACNA1C-Related Disorders (CRDs). This shared language helps with diagnosis, care and research.

What is Timothy Syndrome?

Timothy Syndrome (TS) is a well-recognised, often more severe, presentation within the CRD group. It was first described clinically in 1992 and more fully characterised in 2004. 

Consensus statement on language

Typical features:

• A prolonged QT interval on an ECG (electrocardiogram), and
• Neurodevelopmental differences (for example delayed development or autism)

Other possible features: syndactyly (webbed fingers/toes), hypotonia (low muscle tone), seizures, hypoglycaemia, hip differences and dental or facial features.

The best-known variant is p.G406R. It is strongly associated with TS and can occur in different exons. The consensus is clear: TS should be diagnosed on the basis of the clinical syndrome together with genetic evidence, not on variant location alone. 

What are CACNA1C-Related Disorders?

“CRDs” is the umbrella term for people with rare, clinically relevant variants in CACNA1C. Presentations range from:

• mainly cardiac features (for example long QT)
• mainly neurodevelopmental features (for example autism, epilepsy), or
• a mix of features across systems

Because expression and effects vary with tissue and age, two family members with the same variant can look very different. For this reason, a holistic multisystem approach to care is recommended for anyone with a CACNA1C finding. 

Note: short-QT or Brugada-pattern ECGs have been reported in people with CACNA1C variants. The consensus highlights these observations but also makes clear that evidence for CACNA1C as a direct cause of classic Brugada or short-QT syndromes is limited and under debate.

How common are CACNA1C-Related Disorders?

CRDs are ultra-rare. More testing (exome/genome) and rising awareness have increased the number of diagnosed people to well over 250 worldwide. The CACNA1C Community Registry continues to grow.

Diagnosis and testing

Diagnosis is a combination of:

• the clinical picture, and
• a genetic result (pathogenic/likely pathogenic or VUS), guided by published cases

If the classic prolonged QT interval + neurodevelopmental pattern is present with a relevant CACNA1C variant, Timothy Syndrome should be diagnosed after appropriate clinical genetic assessment. Where the picture differs, the term CRD is used. 

Tests used:

• gene panels, or
• whole exome sequencing (WES) / whole genome sequencing (WGS)

Results may be pathogenic/likely pathogenic, VUS, or benign. Classifications can change as knowledge advances.

See specific guidelines for your clinical team.

Syndromic interpretation of CACNA1C pathogenic variants

Figure from “Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement,” Underwood JFG et al., Research Square (2024), licensed under CC BY 4.0.

If you have a Variant of Uncertain Significance (VUS)

A VUS can be hard to understand. The consensus recommends clinicians consider multisystem screening and monitoring when a VUS is found and clinical suspicion exists. Repeat testing and specialist genetic input may reclassify the variant. Families with a VUS are welcome in the community and should be offered follow-up and support.

Care and treatment (what is normally recommended)

•  Annual cardiac and endocrine review, including ECG and echocardiography.
• Beta-blockers and ICDs where clinically indicated; loop recorders for ongoing monitoring in selected cases.
• Glucose monitoring and hypoglycaemia rescue plans.
• Seizure rescue medicines and training for home/school.
• Neurodevelopmental assessments and individual education plans.
• Dental, digestive and infection management as needed.
• Left cardiac sympathetic denervation (stellate ganglionectomy) may be considered in selected high-risk cases.
• Tell anaesthetists in advance — anaesthesia responses can differ.

What to do next

• If you have a pathogenic/likely pathogenic result: ask for a full multisystem review (cardiology, neurology, endocrine, genetics).
• If you have a VUS: ask for re-analysis plans and consider multisystem screening.
• Join the CACNA1C Community Registry and our support group.
• Keep a copy of any ECGs, genetic reports and hospital letters for future re-review.

LoF variants

Timothy Syndrome is characterised by Gain of Function (GoF) variants in the CACNA1C gene, however, there are also individuals with CACNA1C-related disorders who have Loss of Function (LoF) variants.

In a Gain of Function variant, the calcium channels open and stay open for a long time. As a result, calcium ion influx is increased, causing increased neuronal excitability.

In a Loss of Function variant, the opposite occurs; there is improper channel opening, resulting in less calcium entering the cells and decreased neuronal firing.

Loss of Function CACNA1C variants can lead to Short QT (SQT), a highly lethal heart rhythm disturbance that is the mirror image of Long QT (prolonged QT interval), one of the hallmark features of Timothy Syndrome.

Background

Timothy Syndrome is named after Katherine Timothy who first described the condition.

While conducting a study on Long QT Syndrome, Katherine identified a very small subset of infants who had extremely prolonged QT intervals and always presented at birth with syndactyly or conjoined fingers and toes.

The DNA of these children was collected and entered into every possible genetic study for almost 20 years. In 2004, the discovery was finally made.

Each child shared an identical genetic change in the L-type Calcium Channel gene, CACNA1C. This condition came to be known as Timothy Syndrome.

This website contains general information about CACNA1C-related disorders. The information is not advice, and should not be treated as such. You must not rely on the information on this website as an alternative to medical advice from your relevant medical professional. TSA does not promote or recommend any treatment, therapy, institution or health care plan.

The information contained in this site is intended for your general education and information only. Any treatment plan for any given patient must be carried out on an individual basis, after a thorough discussion with the patient’s medical professional(s).