Timothy syndrome is a rare autosomal-dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing of fingers and toes), and autism spectrum disorders. Timothy syndrome represents one clinical manifestation of a range of disorders associated with mutations in CACNA1C, the gene encoding the calcium channel Cav1.2 α subunit. Signs and symptoms The most striking sign of Timothy syndrome type 1 is the co-occurrence of both syndactyly (about 0.03% of births) and long QT syndrome (1% per year) in a single patient. Other common symptoms include cardiac arrhythmia (94%), heart malformations (59%), and autism or an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in about half of patients. Children with this disorder have small teeth, which is due to poor enamel coating, are prone to dental cavities and often require removal. The average age of death due to complications of these symptoms is 2.5 years, although there have been multiple reports of patients living in to their mid- or late-twenties. Timothy syndrome type 2 has largely the same symptoms as the classical form. Differences in the type 2 form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and often hip dysplasia. Patients with Timothy syndrome type 2 also have more facial deformities, including protruding foreheads and tongues. Children with Timothy syndrome tend to be born via caesarean section due to fetal distress. Pathophysiology There are two recognized types of Timothy syndrome, classical (type-1) and a second type (type-2). They are both caused by mutations in CACNA1C, the gene encoding the calcium channel Cav1.2 α subunit. Timothy syndrome mutations in CACNA1C cause delayed channel closing, also known as voltage-dependent inactivation, thus increased cellular excitability. Both types of Timothy syndromes are caused by mutations in CACNA1C. These mutations are in exon 8 (type 2) and exon 8a (classical form, type 1). Exons 8 and 8A are mutually exclusive exons. Exon 8a is highly expressed in the heart, brain, gastrointestinal system, lungs, immune system, and smooth muscle. Exon 8 is also expressed in these regions and its level is roughly five-fold higher than exon 8a expression. One mutation is found in patients with classical Timothy syndrome, G406R, located just past the sixth membrane-spanning segment of domain 1 (D1S6). The conserved glycine at this position seems