SNP Shot: Genomic Insights

Timothy syndrome is a rare, often life-threatening disorder that primarily affects the heart but can impact other parts of the body. The severity of the condition varies from person to person.

A key feature of Timothy syndrome is long QT syndrome, a heart condition where the heart muscle takes an extended time to recharge between beats. This electrical abnormality in the heart can lead to severe heart rhythm problems (arrhythmias), potentially causing sudden death. Some individuals with Timothy syndrome are also born with structural heart defects (cardiomyopathy) that impair the heart's ability to pump blood effectively.

Due to these serious heart issues, some individuals with Timothy syndrome survive only into childhood. Ventricular tachycardia, a dangerous type of arrhythmia where the lower heart chambers (ventricles) beat too rapidly, accounts for approximately 80% of Timothy syndrome deaths. This arrhythmia can lead to cardiac arrest (the heart stopping) and sudden death.

Timothy syndrome is also characterized by cutaneous syndactyly, which is webbing or fusion of the skin between certain fingers or toes. About half of those affected have distinctive facial features, including a flattened nasal bridge, low-set ears, a small upper jaw, and a thin upper lip. Children with Timothy syndrome may have small, misplaced teeth and are prone to frequent cavities (dental caries). Additional signs and symptoms can include baldness at birth, low muscle tone (hypotonia), frequent infections, episodes of low blood sugar (hypoglycemia), and abnormally low body temperature (hypothermia). The respiratory and gastrointestinal systems can also be affected.

Neuropsychiatric issues are also frequently seen in people with Timothy syndrome. Research indicates that many children with the syndrome exhibit characteristics of autism spectrum disorders. These children often experience impaired communication and socialization skills, as well as delays in speech and language development. Poor coordination is also common. Other nervous system disorders that may occur include attention-deficit/hyperactivity disorder, intellectual disability, and recurrent seizures (epilepsy). Some individuals may have photosensitive epilepsy, where seizures are triggered by flashing lights.

Inheritance:

Timothy syndrome follows an autosomal dominant inheritance pattern. This means that only one copy of a mutated CACNA1C gene in each cell is enough to cause the condition. In most cases, the condition arises from new (de novo) mutations in the gene, meaning there's no family history of the disorder. Because Timothy syndrome is so severe, it's rare for an affected person to pass the altered gene on to their children. In rare instances, someone with Timothy syndrome may inherit the altered gene from a parent who is a mosaic for the CACNA1C gene variant. Mosaicism means the parent carries the variant in some cells (including egg or sperm cells) but not in others.