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Timothy syndrome
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Timothy syndrome

Timothy syndrome is a rare multisystem disorder marked by life‑threatening cardiac arrhythmias and distinctive physical and neurodevelopmental features.

Overview

Timothy syndrome is a rare disorder that primarily affects the heart but can involve many other organ systems. The condition is often life‑threatening because of severe cardiac arrhythmias, and individuals may also present with characteristic facial features, dental problems, skin webbing, and neuropsychiatric manifestations.

Symptoms

  • Long QT syndrome – prolonged cardiac repolarization leading to arrhythmias.
  • Severe arrhythmias, including ventricular tachycardia that can cause sudden cardiac arrest.
  • Structural heart defects (cardiomyopathy) affecting cardiac output.
  • Cutaneous syndactyly – webbing or fusion of the skin between fingers or toes.
  • Distinctive facial features: flattened nasal bridge, low‑set ears, small upper jaw, and other dysmorphic traits.
  • Dental abnormalities: small upper jaw and frequent cavities (dental caries).
  • Baldness at birth.
  • Low muscle tone (hypotonia).
  • Frequent infections.
  • Episodes of low blood glucose (hypoglycemia).
  • Abnormally low body temperature (hypothermia).
  • Respiratory and gastrointestinal involvement.
  • Neuropsychiatric features:
    • Autism spectrum disorder characteristics (impaired communication, socialization, delayed speech).
    • Poor coordination.
    • Attention‑deficit/hyperactivity disorder (ADHD).
    • Intellectual disability.
    • Recurrent seizures (epilepsy), including photosensitive epilepsy triggered by flashing lights.

Causes & Risk Factors

Pathogenic variants in the CACNA1C gene cause Timothy syndrome. This gene encodes the CaV1.2 L‑type calcium channel, a pore that transports calcium ions into cardiac and neuronal cells. Mutations produce channels that remain open longer than normal, leading to calcium overload, abnormal cardiac electrical activity, and disrupted regulation of developmental genes, which together generate the cardiac, facial, dental, and neurological manifestations of the disorder.

Some CACNA1C variants may produce isolated features—such as only long QT syndrome or only neurodevelopmental disorders—without the full spectrum of Timothy syndrome.

Inheritance

Timothy syndrome follows an autosomal dominant pattern; a single altered copy of CACNA1C is sufficient to cause disease. Most cases arise from de novo mutations with no family history. Because the condition is often severe, affected individuals rarely transmit the variant, though rare instances of parental mosaicism have been reported.

Frequency

Timothy syndrome is extremely rare, with fewer than 100 reported cases worldwide.

Other Names

  • Long QT syndrome with syndactyly
  • LQT8
  • TS

Additional Information & Resources

Genetic Testing

  • Genetic Testing Registry: Timothy syndrome

Patient Support

  • National Organization for Rare Disorders (NORD)

Scientific References

  • Bauer R, Timothy KW, Golden A. Update on the Molecular Genetics of Timothy Syndrome. Front Pediatr. 2021 May 17;9:668546. doi:10.3389/fped.2021.668546.
  • Herold KG, Hussey JW, Dick IE. CACNA1C-Related Channelopathies. Handb Exp Pharmacol. 2023;279:159-181. doi:10.1007/164_2022_624.
  • Levy RJ, Timothy KW, Underwood JFG, et al. A Cross‑Sectional Study of the Neuropsychiatric Phenotype of CACNA1C‑Related Disorder. Pediatr Neurol. 2023 Jan;138:101-106. doi:10.1016/j.pediatrneurol.2022.10.013.
  • Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995 Oct 1;76(10):744-5. doi:10.1016/s0002-9149(99)80216-1.
  • Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995 Jan;25(1):59-64. doi:10.1016/0735-1097(94)00318-k.
  • Napolitano C, Priori SG. CACNA1C‑Related Disorders. GeneReviews® (2025 Sep 18).
  • Splawski I, Timothy KW, Decher N, et al. Severe arrhythmia disorder caused by cardiac L‑type calcium channel mutations. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8089-96. doi:10.1073/pnas.0502506102.
  • Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004 Oct 1;119(1):19-31. doi:10.1016/j.cell.2004.09.011.

Frequently Asked Questions

The mutation in the CACNA1C gene causes calcium channels to stay open too long, leading to calcium overload in cells. This affects not just the heart but also the brain and other tissues, resulting in a complex daily management routine. Patients often require strict monitoring of blood sugar levels to prevent hypoglycemia, careful temperature regulation to avoid hypothermia, and specialized dental care due to frequent cavities and jaw abnormalities. Neurodevelopmental challenges, such as autism spectrum traits, ADHD, and photosensitive epilepsy, mean that daily life may require sensory-friendly environments, structured routines, and avoidance of flashing lights or strobe effects that could trigger seizures.
Timothy syndrome is caused by a pathogenic variant in the CACNA1C gene. In most cases, the condition occurs as a de novo (new) mutation, meaning it is not inherited from a parent and the parents do not carry the gene change. However, if a parent does have the mutation, there is a 50 percent chance of passing it to each child. Genetic counseling is strongly recommended for families to understand the specific inheritance pattern of their case and to discuss options for prenatal or preimplantation genetic testing for future pregnancies.
Parents and caregivers should be vigilant for episodes of fainting (syncope), sudden loss of consciousness, or unexplained lethargy. Because the arrhythmias can lead to ventricular tachycardia and sudden cardiac arrest, any instance where the child becomes unresponsive or has a seizure-like episode without a clear febrile trigger is a medical emergency requiring immediate activation of emergency services. Additionally, signs of poor circulation such as pale or blue-tinged skin and rapid, irregular breathing during an episode are critical indicators that the heart is not pumping effectively.
Due to the high risk of photosensitive epilepsy, it is crucial to minimize exposure to flashing lights, strobe effects, and certain video games or digital screens that may trigger seizures. Additionally, because individuals with Timothy syndrome often have hypothermia (abnormally low body temperature) and hypoglycemia (low blood sugar), maintaining a warm environment and ensuring regular, timely meals are essential. Caregivers should also be mindful of the child's potential for poor coordination and low muscle tone, ensuring that home environments are safe from fall hazards and that physical activities are supervised to prevent injury.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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