Timothy Syndrome

A number sign (#) is used with this entry because of evidence that Timothy syndrome (TS) is caused by heterozygous mutation in the CACNA1C gene (114205) on chromosome 12p13.

Mutation in the CACNA1C gene can also cause Brugada syndrome (BRGDA3; 611875) and long QT syndrome (LQT8; 618447).


Timothy syndrome (TS) is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism (Splawski et al., 2004).

Clinical Features

Reichenbach et al. (1992) and Marks et al. (1995) described 3 male and 2 female infants with long QT syndrome, syndactyly, and a high risk of sudden death. Four died suddenly at an early age. All 5 had transient 2:1 atrioventricular block. AV block had previously been reported in long QT syndrome and results from prolonged ventricular repolarization rather than an intrinsic conduction disturbance. The family history was negative in each case. New dominant mutation, recessive inheritance, or a contiguous gene syndrome were considered possibilities. The first patient had a small patent ductus arteriosus (see 607411) by echocardiogram; the second had a tiny membranous ventricular septal defect and patent foramen ovale by echocardiogram. Marks et al. (1995) commented that atrioventricular block occurs in patients with long QT syndrome as a result of prolonged ventricular repolarization rather than an intrinsic conduction abnormality.

Splawski et al. (2004) referred to the disorder reported by Reichenbach et al. (1992) and Marks et al. (1995) as Timothy syndrome (TS) and described 17 affected children. Inheritance was sporadic in all but 1 family in which 2 of 3 sibs were affected. None of the parents was affected. Ten of the 17 children with TS died, and the average age of death was 2.5 years. All affected individuals had severe prolongation of the QT interval on electrocardiogram, syndactyly, and abnormal teeth and were bald at birth. Arrhythmias were the most serious aspect of TS, and 12 of 17 children had life-threatening episodes. Individuals with TS also had congenital heart disease, including patent ductus arteriosus, patent foramen ovale, ventricular septal defects, and tetralogy of Fallot. Some children had dysmorphic facial features, including flat nasal bridge, small upper jaw, low-set ears, or small or misplaced teeth. Episodic serum hypocalcemia was described in 4 individuals. Many of the surviving children showed developmental delays consistent with language, motor, and generalized cognitive impairment, and Splawski et al. (2004) demonstrated a significant association between autism spectrum disorders and TS.

Splawski et al. (2005) studied 2 children with Timothy syndrome without syndactyly. The first was a girl who had bradycardia, biventricular hypertrophy, and moderate biventricular dysfunction noted at 25 weeks' gestation, with 2:1 atrioventricular block and QTc of 730 ms noted at birth. Despite placement of an implantable pacemaker, she had multiple episodes of severe arrhythmias requiring cardioversion or resuscitation in infancy. Cervical sympathetic ganglionectomy and ventricular pacemaker placement at 4 months of age were unsuccessful in reducing arrhythmias. She had bilateral congenitally dislocated hips and joint hyperextensibility, and muscle biopsy at age 5 months revealed nemaline myopathy. By age 6 years, a discrepancy of body development was apparent, with her lower body typical of a 2- to 3-year-old child. Facial dysmorphism included protruding forehead, depressed nasal bridge, and protruding tongue, and severe caries resulted in the extraction of most teeth. She also experienced seizures with increasing frequency, static encephalopathy, and severe developmental delay. She died at age 6 years due to ventricular fibrillation. The second child was a boy who was apparently well until age 4 years, when he experienced cardiac arrest while at play and was diagnosed with long QT syndrome. Over the next 6 years, he had 3 more episodes of cardiac arrest, all triggered by auditory stimuli, and underwent pacemaker implantation. At age 11, he experienced cardiac arrest after antibiotic therapy and was in a coma for 2 weeks, following which significant brain damage remained. An implantable cardioverter defibrillator (ICD) was placed that subsequently fired more than 20 times. At age 21, he was still experiencing weekly cardiac arrhythmias, which were associated with night terrors, and he exhibited signs of depression and obsessive-compulsive behavior.

Hiippala et al. (2015) studied a 13-year-old Finnish girl who was resuscitated from ventricular fibrillation after collapsing at home and was found to have a slightly prolonged QTc interval of 480 ms. She had a history of 2 similar events in the previous year while walking with friends, from which she recovered spontaneously. Cardiac evaluation showed normal structure and function, with a peak heart rate of 176 bpm on exercise testing, which did not trigger any ventricular arrhythmias. Flecainide provocation and adrenaline infusion tests were negative. An ICD was inserted, but over a follow-up period of 3.5 years, no shocks occurred, and her QTc intervals were in the high-normal range (440 to 460 ms). She had no learning difficulties or psychiatric disorders, no craniofacial dysmorphism, and no musculoskeletal abnormalities.

Molecular Genetics

Splawski et al. (2004) showed that, in all available patients, TS resulted from an identical de novo gly406-to-arg (G406R; 114205.0001) mutation in exon 8A of the CACNA1C gene. They found that CACNA1C was expressed in all tissues affected in TS. Functional expression revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. Splawski et al. (2004) stated that this likely induces intracellular Ca(2+) overload in multiple cell types. They noted that, in the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in TS. These findings established the importance of CACNA1C in human physiology and development and implicated Ca(2+) signaling in autism.

Splawski et al. (2005) reported 2 individuals with a severe variant of TS in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene (G406R, and G402S, 114205.0002). They found that the exon 8 splice variant was highly expressed in heart and brain, accounting for about 80% of CACNA1C mRNA. In contrast to previously reported TS patients with a mutation in exon 8A, these 2 patients did not have syndactyly, had an average QT interval that was 60 ms longer, and had multiple episodes of unprovoked arrhythmia; multiple arrhythmias were rare in the patients with mutations in exon 8A, and most were associated with medications and/or anesthesia. Splawski et al. (2005) concluded that gain-of-function mutations in CACNA1C exons 8 and 8A cause distinct forms of TS; they designated the atypical, more severe form due to exon 8 mutations 'TS2' (Timothy syndrome type 2).

To explore the effect of the Timothy syndrome G406R mutation in the CaV1.2 channel on the electrical activity and contraction of human cardiomyocytes, Yazawa et al. (2011) reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated those cells into cardiomyocytes. Electrophysiologic recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients in ventricular-like cells. Yazawa et al. (2011) found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2, restored the electrical and calcium signaling properties of cardiomyocytes from Timothy syndrome patients. Yazawa et al. (2011) concluded that their study provided new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans and provided a robust assay for developing drugs to treat these diseases.

Etheridge et al. (2011) studied a severely affected infant with Timothy syndrome and his mildly affected father. The father never experienced syncope or seizure, but had cutaneous syndactyly of the toes and was found to have a prolonged QTc (480 ms). The authors also studied an unrelated, moderately affected 14-year-old girl; she experienced cardiac arrest with documented ventricular fibrillation and a QTc of 560 ms in adolescence, and had bilateral syndactyly of the hands and feet. All 3 patients were heterozygous for the G406R mutation in the CACNA1C gene; however, the 2 more mildly affected individuals were both found to be mosaic for the mutation, showing only a minor peak for the mutant allele. Analysis of the father's gametes revealed that approximately 16% of his sperm carried the mutant allele; cardiac tissue was not available for study. Etheridge et al. (2011) noted that previously described 'de novo' mutations in Timothy syndrome might also represent cases of parental mosaicism, with implications for genetic counseling.

By targeted sequencing of channelopathy- and arrhythmogenic right ventricular cardiomyopathy (see 107970)-associated genes in a 13-year-old Finnish girl who had cardiac arrest due to ventricular fibrillation and QTc intervals in the upper limits of normal, and who was negative for the 4 most common Finnish LQTS mutations, Hiippala et al. (2015) identified heterozygosity for the G402S mutation in the CACNA1C gene. Her unaffected parents, who had normal electrocardiograms, did not carry the mutation. To evaluate the possibility of mosaicism, Hiippala et al. (2015) calculated the ratio of mutated and normal alleles from the next-generation sequencing (NGS) reads, and found that 37% of the reads represented the mutated allele and 61% showed the normal allele. Sanger sequencing of blood- and saliva-derived DNA confirmed the mutation; in both samples, the mutation peak was slightly weaker than the normal genotype, consistent with the allele distribution detected by NGS.


Erxleben et al. (2006) noted that the CaV1 family of calcium channels has a second mode of gating, termed 'mode 2,' that involves frequent openings of much longer duration than 'mode 1.' Cyclosporin, a calcineurin (see 114105) inhibitor, and a mutation associated with Timothy syndrome independently resulted in increased mode 2 activity in recombinant rabbit CaV1.2 channels. Stimulation of mode 2 activity was blocked by inhibition of calcium/calmodulin-dependent protein kinase-2 (CAMK2A; 114078) and by mutating putative phosphoacceptor serine residues at the cytoplasmic end of the S6 helix in domain I (Timothy syndrome) or domain IV (cyclosporin), which both contain consensus sequences for CAMK2A. Erxleben et al. (2006) concluded that aberrant phosphorylation and increased cellular calcium entry contribute to the neurotoxicity observed in some transplant patients with chronic cyclosporin use, and that a similar excitotoxic mechanism is at work in patients with Timothy syndrome.


Splawski et al. (2004) named this disorder Timothy syndrome in honor of Dr. Katherine W. Timothy, who was among the first to identify a case of severe long QT syndrome and syndactyly and performed much of the phenotypic analysis that revealed other abnormalities (Keating, 2004).