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).

Bauer et al. (2021) reviewed the genetic and clinical findings in published reports of Timothy syndrome, noting that although classically TS is characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay, an increasing number of identified TS-causing variants are associated with complex and variable symptom profiles, including some cases exhibiting only cardiac features. Potential mechanisms for the variability observed in clinical features include mosaicism, genetic background, isoform complexity of CACNA1C with differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. The authors proposed a TS nomenclature based on specific mutation designations, but noted that the case reports could also be grouped as a single entity, Timothy syndrome, with the recognition that there is a broad and variable phenotypic spectrum.

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 (PDA) by echocardiogram; the second had a tiny membranous ventricular septal defect (VSD) and patent foramen ovale (PFO) 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 (ECG), 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 PDA, PFO, VSD, 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 with mutation in the CACNA1C gene. 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.

Gillis et al. (2012) reported a severely affected boy with QT prolongation, syndactyly of the hands and feet, dysmorphic features, developmental delay, and mutation in the CACNA1C gene. Multiple dysmorphisms were evident at birth, including round face, thin lips, micrognathia, contractures of the limbs and decreased range of motion at joints, bilateral dislocated hips, clenched hands with cutaneous syndactyly of the fingers, and planovalgus position of the feet with cutaneous syndactyly of the toes. Neurologic evaluation showed abnormal posturing and movements, absence of neonatal reflexes, preferential gaze to the right, and no response to loud noise. The proband had intermittent hypoglycemia, hypocalcemia, seizures, and cardiac arrhythmias, with self-limited episodes of polymorphic ventricular tachycardia, 2:1 atrioventricular block, and marked QT prolongation. He also experienced a stroke in the first week of life, with acute infarction involving the left hemisphere on brain MRI. At 4 years of age he continued to have prolonged QT intervals, was G-tube-dependent for feeding, had cortical blindness and intractable seizures, and was profoundly developmentally delayed with very little spontaneous movement. Glucose and calcium levels had remained stable.

Hiippala et al. (2015) studied a 13-year-old Finnish girl who had a prolonged QT interval with syncopal episodes, and mutation in the CACNA1C gene. She 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.

Boczek et al. (2015) reported a boy who died at age 3.75 years with Timothy syndrome and mutation in the CACNA1C gene. At birth he exhibited bradycardia with 2:1 atrioventricular block and marked ventricular repolarization delay, with QT intervals ranging from 595 to 812 ms, and underwent placement of an ICD, left sympathectomy, and PDA ligation at 1 month. He experienced infantile spasms and later, apneic seizures, with good control ultimately achieved on a ketogenic diet. At age 7 months, he had severe asymmetric septal hypertrophy that resolved with discontinuation of corticosteroids and a change in antiepileptic medication. Repeat echocardiogram at age 3.75 years showed normal cardiac size, thickness, and function. Brain CTs showed progressive cerebral and cerebellar atrophy from age 10 months to 28 months, and he had intellectual impairment. Facial dysmorphisms included prominent forehead, hypertelorism, flattened nasal bridge, short nose, small tented mouth, hypotonic facies, and sparse hair. He had joint hypermobility including of the fingers, as well as dimpling at the elbow and shoulder joints, clinodactyly, short thumbs, bilateral metatarsus adductus, osteopenia, hypotonia, and cryptorchidism. He also had severely hypoplastic teeth and decay, with extraction of 20 teeth at 2.5 years of age. Analysis of the primary dentition (Papineau and Wilson, 2014) showed soft poorly formed enamel, decay in hypoplastic areas and on occlusal surfaces of partially erupted molars, and gingival hyperplasia; radiographs revealed taurodontism in all primary first molars. He underwent multiple hospital admissions for respiratory failure, and ultimately died at age 3.75 years with respiratory failure, hypotension, and dehydration.

Ozawa et al. (2018) described a 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, autistic spectrum disorder, and mutation in the CACNA1C gene. Facial dysmorphisms included round face, flat nose, and low-set ears; he did not have syndactyly. He experienced cardiopulmonary arrest at age 13 years, from which he was resuscitated; review of ECGs recorded at ages 6, 9, and 12 years all showed QT interval prolongation, with QTc ranging from 471 to 500 ms. On the third day after his cardiac arrest, echocardiogram showed left ventricular apical ballooning, and he experienced recurrent episodes of torsades de pointes and ventricular fibrillation (VF); he then underwent placement of an ICD. In 2 years of follow-up without medication therapy, there was no shock for VF.

Ye et al. (2019) reported a 14-year-old boy with QT prolongation, bradycardia, seizures, autism spectrum disorder, and mutation in the CACNA1C gene. He also had unexplained hyperglycemia. ECG showed QTc of 486 ms, and he underwent left cardiac sympathetic denervation due to intolerance of beta blockers. The authors noted that there was never a prolonged PR interval or evidence of a Brugada pattern on his ECGs. Because of progressively more severe bradycardia and frequent changes in T-wave polarity observed on an implantable loop recorder, he underwent implantation of a defibrillator. The authors designated the proband's phenotype as LQT8, stating that it was unclear whether his autism spectrum disorder and unexplained hyperglycemia were related to his CACNA1C mutation.

Clinical Variability

Boczek et al. (2015) reported 3 families in which affected individuals with mutation in the CACNA1C gene exhibited varying combinations of QT prolongation, hypertrophic cardiomyopathy (CMH), congenital heart defects, and sudden cardiac death (SCD). None of the family members had syndactyly, cognitive impairments, facial dysmorphisms, or other noncardiac clinical characteristics suggestive of TS. In pedigree 1, the proband was a 33-year-old woman with a history of ventricular septal defect who presented at age 25 years with QT prolongation during pregnancy and a family history of SCD. She underwent implantation of a cardioverter/defibrillator. She later experienced peripartum cardiomyopathy after giving birth to triplets, and echocardiography several years later showed ventricular septal hypertrophy. Her father died at age 36 years of a cardiac arrhythmia due to CMH, with cardiac hypertrophy and fibrosis noted at autopsy. A brother who was known to have QT prolongation died at age 24 years due to ventricular fibrillation, and his autopsy revealed CMH with cardiomegaly and interstitial fibrosis. His son had marked QT prolongation, as did the proband's sister. In pedigree 2, the proband was discovered to have QT prolongation when he underwent a screening ECG because his father had been diagnosed with CMH. In pedigree 3, the proband was born with cleft mitral valve and atrial septal defect, and also had QT prolongation; she exhibited intraoperative torsades de pointes following which she underwent implantation of a cardioverter/defibrillator. Her sister, who had obstructive CMH and underwent 2 myectomies before age 5 years, also had QT prolongation and died suddenly at age 30; autopsy showed symmetric cardiac hypertrophy and fibrosis. Their mother had an enlarged septum and QT prolongation, their maternal aunt and cousin were diagnosed with CMH, and their maternal grandfather died suddenly at age 64. The authors designated the phenotype in the 3 families as 'cardiac-only Timothy syndrome (COTS).'

The heterozygous mutations in the CACNA1C gene that were identified in patients with Timothy syndrome by Splawski et al. (2004) occurred de novo.

The transmission pattern of Timothy syndrome in the families reported by Boczek et al. (2015) was consistent with autosomal dominant inheritance.

In 13 patients with Timothy syndrome from whom DNA samples were available, Splawski et al. (2004) identified heterozygosity for a de novo missense mutation (G406R; 114205.0001) in the alternatively spliced 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). CACNA1C has alternatively spliced transcripts that are encoded by 2 mutually exclusive exons, 8 and 8A. 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 the G406R 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).

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 alternatively spliced exon 8A of 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.

In a severely affected boy with QT prolongation, syndactyly, stroke, and profound developmental delay, Gillis et al. (2012) sequenced the CACNA1C gene and identified a de novo missense mutation, A1473G.

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 exon 8 of 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 proband's 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.

In a boy who died at age 3.75 years with QT prolongation and a Timothy syndrome phenotype, in whom analysis of an LQT gene panel was negative, including exons 8, 8A, and 9 of the CACNA1C gene, Boczek et al. (2015) performed whole-exome sequencing (WES) and identified heterozygosity for a de novo missense mutation in exon 27 of the CACNA1C gene (I1166T; 114205.0015). Sanger sequencing confirmed the mutation and its absence in his parents; the variant was also not present in public variant databases. Functional analysis revealed a novel electrophysiologic phenotype distinct from that of classic TS mutations, which result in almost complete loss of inactivation of CaV1.2 channels. Instead, the I1166T mutation causes an overall loss of current density with a gain-of-function shift in activation, resulting in an increased window current. The authors noted that although extracardiac differences had been observed across various TS-associated CACNA1C mutations, the cardiac phenotype appeared to be consistent, with QT prolongation, arrhythmias, cardiac hypertrophy, and PDA being commonly reported.

In a 3-generation family (pedigree 1) in which 5 individuals had QT prolongation, CMH, congenital heart defects, and/or sudden cardiac death, Boczek et al. (2015) performed WES and identified heterozygosity for a missense mutation in exon 12 of the CACNA1C gene (R518C; 114205.0016) that segregated fully with disease. The authors then sequenced CACNA1C exon 12 in 5 probands with QT prolongation and a personal or family history suggestive of CMH, and identified heterozygosity for the same R518C mutation in a father with CMH and his son with QT prolongation (pedigree 2). In addition, another mutation at the same residue, R518H (114205.0017), was found in heterozygosity in 2 affected sisters and their affected cousin (pedigree 3). Functional analysis showed that the R518C/H variants result in a complex electrophysiologic phenotype including an overall loss of current density, increased window and late currents, and decelerating voltage-dependent inactivation resulting in constitutively active L-type calcium channels.

In a 14-year-old Japanese boy with a prolonged QT interval, dysmorphic facial features, intellectual disability, seizures, and autism spectrum disorder, Ozawa et al. (2018) screened a gene panel and identified heterozygosity for a de novo missense mutation in the CACNA1C gene (S643F; 114205.0018). Sanger sequencing confirmed the mutation and its absence in his unaffected parents and sibs, and it was not present in public variant databases. Functional analysis demonstrated an increase in late CaV1.2 currents as well as a marked reduction in peak currents with the S643F mutant compared to wildtype CACNA1C. In addition, the S643F channels never reached a fully inactivated state, with an inactivation level of 42% at maximum.

In a 14-year-old boy with QT prolongation, bradycardia, seizures, and autism spectrum disorder, Ye et al. (2019) analyzed a 13-gene LQTS panel and identified heterozygosity for a missense mutation in the CACNA1C gene (E1115K; 114205.0019). The mutation was not found in his unaffected mother or half sibs, or in the gnomAD database; DNA was unavailable from his father. Functional analysis showed that the mutation eliminates intrinsic calcium channel activity and converts the L-type calcium channel into a nonselective monovalent cation channel, with marked increases in both peak and persistent inward sodium currents and outward potassium/cesium currents.

Variant Function

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.

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).