Familial long QT syndrome
-Rare cardiac disease
-Rare genetic disease
Comment:
Timothy syndrome (LQT8) is a sub-type of familial long QT syndrome. It is a severe multi-organ system disorder characterized by long QT syndrome with associated tachyarrhythmia, facial, and neurodevelopmental features. Two sub-types of Timothy syndrome are described, both with heterozygous gain-of-function mutation in exon 8 of CACNA1C, encoding the alpha 1C subunit of the L-type calcium channel. Type 1 is caused by a mutation in exon 8A of CACNA1C gene (mainly p.Gly406Arg) and associates with syndactyly (PMID:26227324). Type 2 is caused by mutations in the alternatively spliced exon 8 of the CACNA1C gene (mainly p.Gly406Arg or p.Gly402Ser) and is characterized by an extremely long QT interval greater than 500ms and the absence of syndactyly (PMID:24960393).
Timothy syndrome 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).
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 ... 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 been previously 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. (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 ... 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 (see 114205.0001 and 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. To explore the effect of the Timothy syndrome mutation gly406 to arg (114205.0001) 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.
Timothy syndrome is a multisystem disorder characterized by cardiac, hand, facial, and neurodevelopmental features caused by mutations in the CaV1.2 L-type calcium channel gene, CACNA1C. Two forms of Timothy syndrome have been described: the classic type (type 1) and a second form caused by mutations in an alternatively spliced form (type 2)....
DiagnosisClinical DiagnosisTimothy syndrome is a multisystem disorder characterized by cardiac, hand, facial, and neurodevelopmental features caused by mutations in the CaV1.2 L-type calcium channel gene, CACNA1C. Two forms of Timothy syndrome have been described: the classic type (type 1) and a second form caused by mutations in an alternatively spliced form (type 2).Classic Timothy syndrome (type 1) is suspected in an individual with the following two constant features:A rate-corrected QT (QTc) interval of between 480 ms and 700 msUnilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and threeAdditional findings that may be present:Congenital heart defects (patent ductus arteriosus [PDA], patent foramen ovale [PFO], ventricular septal defect [VSD], tetralogy of Fallot [TOF], hypertrophic cardiomyopathy [HCM]) (in~61% of individuals)Facial anomalies including flat nasal bridge, low-set ears, thin upper lip, round face (in ~85% of individuals)Neurologic symptoms including autism, seizures, intellectual disability, hypotoniaThe presence of the de novo p.Gly406Arg mutation in the CaV1.2 calcium channel gene CACNA1C confirms the diagnosis of Timothy syndrome [Splawski et al 2004].Timothy syndrome type 2 has been reported in two individuals with CACNA1C mutations in the predominant heart transcript variant, one with an extremely long corrected QT interval (QTc >500 ms) and one with a milder phenotype resulting from somatic cell mosaicism.Molecular Genetic TestingGene. CACNA1C, the gene encoding the CaV1.2 calcium channel, is the only gene in which mutations are known to cause Timothy syndrome [Splawski et al 2004, Splawski et al 2005].Targeted mutation analysisClassic Timothy syndrome (type 1). All 16 individuals with classic Timothy syndrome in whom molecular genetic testing was performed had the same missense mutation, p.Gly406Arg, in exon 8A of CACNA1C [Splawski et al 2004]. Timothy syndrome type 2. The two individuals identified with atypical Timothy syndrome phenotypes had one of two mutations, p.Gly406Arg or p.Gly402Ser, both in exon 8, the predominant heart splice variant of CACNA1C [Splawski et al 2005]. Sequence analysis detects the previously reported missense mutations in Timothy syndrome type 1 and type 2 (see Table 1) along with other sequence variants. Deletion/duplication analysis. The usefulness of deletion/duplication testing has not been demonstrated, as no deletions or duplications involving CACNA1C have been reported to cause Timothy syndrome.Table 1. Summary of Molecular Genetic Testing Used in Timothy Syndrome Type 1 and Type 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1Test AvailabilityType 1Type 2CACNA1CTargeted mutation analysisp.Gly406Arg (exon 8A)100%NAClinicalp.Gly406Arg (exon 8)NAUnknown 2p.Gly402Ser (exon 8)NAUnknown 2Sequence analysisSequence variants 3100%UnknownDeletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletions / duplicationsUnknown; none reported 5Unknown; none reportedNA = not applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. One of two individuals tested to date3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications of CACNA1C have been reported to cause Timothy syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandIdentification of the common mutation p.Gly406Arg in exon 8A of CACNA1C confirms the diagnosis of Timothy syndrome type 1.Identification of the mutation p.Gly406Arg or p.Gly402Ser in exon 8 of CACNA1C confirms the diagnosis of Timothy syndrome type 2.Targeted mutation analysis is performed first. If neither or only one mutation in CACNA1C is identified, sequence analysis of the entire coding region is performed. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in CACNA1C.
Phenotypic features of classic Timothy syndrome are summarized in Table 2 and Table 3 [Reichenbach et al 1992; Marks et al 1995a; Marks et al 1995b; Splawski et al 2004; Lo-A-Njoe et al 2005; Timothy 2005, personal communication; Bloise 2006, personal communication]....
Natural HistoryTimothy Syndrome Type 1Phenotypic features of classic Timothy syndrome are summarized in Table 2 and Table 3 [Reichenbach et al 1992; Marks et al 1995a; Marks et al 1995b; Splawski et al 2004; Lo-A-Njoe et al 2005; Timothy 2005, personal communication; Bloise 2006, personal communication].Cardiac ManifestationsLong QT interval. In addition to QT interval prolongation, electrocardiographic manifestations that are common in individuals with Timothy syndrome and rare in other long QT syndromes (LQTSs) include:Atrioventricular (AV) block. The 2:1 AV block is likely caused by the extremely prolonged ventricular repolarization and refractory periods and not by AV node malfunction.Macroscopic T-wave alternans. Positive and negative T waves on a beat-to-beat basis. This ECG pattern may also be observed in individuals with LQTS3 (SCN5A mutation) and marked prolongation of the QT interval.In general, the diagnosis of Timothy syndrome is made within the first few days of life based on the markedly prolonged rate-corrected QT interval including bradycardia and 2:1 AV block [Reichenbach et al 1992, Marks et al 1995a, Lo-A-Njoe et al 2005]. Rarely, diagnosis may be delayed until age two to four years [Marks et al 1995b, Splawski et al 2005].Occasionally, the diagnosis of Timothy syndrome is suspected prenatally because of fetal distress secondary to cardiac findings of 2:1 AV block or bradycardia with a heart rate that is usually 70-80. (Normal fetal heart rate is 120-150.) In one instance, biventricular hypertrophy and biventricular dysfunction were seen on fetal echocardiogram [Splawski et al 2005].Congenital heart defects are present in approximately 70% of individuals and include PDA, PFO, VSD, TOF, and HCM.Table 2. Cardiac Phenotype of Classic Timothy Syndrome View in own windowCardiac PhenotypeAffected 1/Evaluated%Not AvailableQTc prolongation25/251000TWA7/107015Functional 2:1 AV block17/21814Tachyarrhythmias21/25840Congenital heart disease (PDA, PFO, VSD, TOF, HCM)13/21614TWA = T-wave alternancePDA = patent ductus arteriosus PFO = patent foramen ovaleVSD = ventricular septal defectTOF = Tetralogy of FallotHCM = hypertrophic cardiomyopathy1. n = 25: 13 males, 12 femalesExtracardiac ManifestationsCutaneous syndactyly may involve fingers two (index), three (middle), four (ring), and five (little), and bilateral cutaneous syndactyly of toes two and three. Syndactyly may be unilateral or bilateral and involve fingers four and five only, fingers three through five, or fingers two through five.Craniofacial findingsLow-set earsFlat nasal bridgeSmall upper jawBaldness at birth and for the first two years of life, followed by thin scalp hairSmall, misplaced teeth and poor dental enamel with severe caries [Splawski et al 2004]Neuropsychiatric involvement occurs in approximately 80% of individuals. Developmental delays observed include language, motor, and generalized cognitive impairment. Children were impaired in all areas of adaptive function, including communication, socialization, and daily living skills. Some children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language.Five children were formally evaluated for autism [Splawski et al 2004]. Three met the diagnostic criteria, one met criteria for autism spectrum disorders, and one had severe delays in language development. Other children in this series were deceased or unavailable for evaluation. However, the association between autism spectrum disorders and Timothy syndrome was significant (p = 1.2x10-8). See Table 3.Other findingsFrequent infections (sinus, ear, respiratory) secondary to altered immune responsesIntermittent hypoglycemiaTable 3. Extracardiac Phenotype of Classic Timothy Syndrome View in own windowExtracardiac PhenotypeAffected 1/Evaluated%Not AvailableCutaneous syndactyly25/251000Craniofacial findings 218/21854Sepsis or severe infections11/19576Neuropsychiatric involvement15/19786Autism (FE)3/103015Autism spectrum disorder (FE)2/102015Severe language delay (FE)1/101015Problems in social relationships + mild language delay (FE)2/102015FE= formal evaluation for autism performed 1. n = 25: 13 males, 12 females 2. Low-set ears, flat nasal bridge, small upper jaw, baldness at birth, thin scalp hair, small and misplaced teethCause of death. Ventricular tachyarrhythmia (ventricular tachycardia and ventricular fibrillation), present in 80% of individuals, is the leading cause of death in Timothy syndrome. Average age at death in 14 of 25 children with classic Timothy syndrome was 2.5 years [Reichenbach et al 1992; Marks et al 1995a; Marks et al 1995b; Splawski et al 2004; Lo-A-Njoe et al 2005; Timothy 2005, personal communication; Bloise 2006, personal communication]. In two individuals death not related to tachyarrhythmia has occurred – one from severe infections (despite aggressive antibiotic therapy) and the other from complications of intractable hypoglycemia.Timothy Syndrome Type 2Reported in two individuals [Splawski et al 2005], atypical Timothy syndrome (type 2) is characterized by: (1) presence of extreme prolongation of the QT (QTc ranging from 620 to 730 ms), causing multiple arrhythmias and sudden death; and (2) absence of syndactyly. One child had severe intellectual disability and nemaline rods on muscle biopsy that were considered secondary to prolonged immobility rather than a primary muscle disorder.
The classic (type 1) Timothy syndrome phenotype results from the p.Gly406Arg mutation in exon 8A of CACNA1C. Exon 8A is the alternative splice variant found in approximately 20% of all cardiac mRNAs. Compared to Timothy syndrome type 2, classic Timothy syndrome has milder cardiac symptoms with an average QTc of 580 ms, rare multiple arrhythmias, and association of most arrhythmias with medications and/or anesthesia....
Genotype-Phenotype CorrelationsThe classic (type 1) Timothy syndrome phenotype results from the p.Gly406Arg mutation in exon 8A of CACNA1C. Exon 8A is the alternative splice variant found in approximately 20% of all cardiac mRNAs. Compared to Timothy syndrome type 2, classic Timothy syndrome has milder cardiac symptoms with an average QTc of 580 ms, rare multiple arrhythmias, and association of most arrhythmias with medications and/or anesthesia.In contrast, the two individuals with atypical (type 2) Timothy syndrome had mutations in splice variants that represent 80% of all cardiac mRNAs, resulting in a more severe phenotype than classic Timothy syndrome with an average QTc of 640 ms and multiple episodes of unprovoked arrhythmia.The milder phenotype of the second individual with atypical Timothy syndrome reported by Splawski et al [2005] is attributed to somatic mosaicism (in which the mutation is present in some, not all, cells).
Long QT syndromes. Each of the following LQT syndromes is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes (TdP) ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death....
Differential DiagnosisLong QT syndromes. Each of the following LQT syndromes is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes (TdP) ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death.Romano-Ward syndrome (autosomal dominant long QT syndrome) is characterized by QT interval prolongation. The most common symptom is TdP, which causes a syncopal event and is usually self-terminating. Syncope typically occurs without warning. In some instances, TdP degenerates to ventricular fibrillation, cardiac arrest, and sudden death if the individual is not defibrillated. Approximately 50%-70% of individuals with a disease-causing mutation in one of the genes associated with Romano-Ward syndrome have symptoms; cardiac events may occur from infancy through middle age but are most common from the pre-teen years through the 20s. Romano-Ward syndrome is inherited in an autosomal dominant manner. Most individuals diagnosed with Romano-Ward syndrome have an affected parent. The proportion of cases caused by de novo mutations is small.Andersen-Tawil syndrome (long QT syndrome type 7) is characterized by a triad of features: periodic paralysis (episodic flaccid muscle weakness); prolonged QT interval and ventricular arrhythmias; and dysmorphic features including low-set ears, ocular hypertelorism, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. In the first or second decade, affected individuals present with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Approximately 60% of individuals with Andersen-Tawil syndrome have a detectable mutation in KCNJ2, which encodes the inward rectifier potassium channel protein, Kir2.1. KCNJ2 mutations may also cause the Romano-Ward phenotype. Andersen-Tawil syndrome is inherited in an autosomal dominant manner. At least 50% of diagnosed individuals have an affected parent; the remaining cases are caused by de novo mutations.Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and LQTc usually greater than 500 msec. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. More than half of untreated children with JLNS die prior to age 15 years. The genes in which mutations cause JLNS are KCNQ1 and KCNE1, both of which can also cause Romano-Ward syndrome. JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS may be heterozygotes. Rarely, only one parent may be a carrier; and the other mutation may arise de novo. Parents may or may not have the LQTS phenotype.Syndactyly. Cutaneous syndactyly of the fingers and cutaneous syndactyly of toes two and three can both be seen in numerous disorders. The latter is seen in Bardet-Biedl syndrome and Smith-Lemli-Opitz syndrome, in which it can be a significant clue to diagnosis.Autism. See Autism Overview.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Timothy syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Timothy syndrome, the following evaluations are recommended:ElectrocardiogramEchocardiogramDevelopmental assessmentDysmorphology evaluationTreatment of ManifestationsLong QT intervalBeta-blockers. Most individuals with Timothy syndrome are treated with beta-blockers to maintain QT interval stability and thereby prevent ventricular tachyarrhythmia. However, no data concerning their effectiveness are available. Pacemaker. To control 2:1 AV block and resultant bradycardia, a pacemaker can be placed with general success within the first days of life.Implantable cardioverter defibrillator is most important in preventing sudden cardiac death in individuals with Timothy syndrome. The implant should be considered in every individual with confirmed diagnosis as soon as body weight allows the procedure (as determined by the treating clinician).Congenital heart defects. Standard treatment is indicated.Respiratory infections. Standard treatment (antibiotic therapy, steroids) is indicated.Prevention of Primary ManifestationsArrhythmias in Timothy syndrome must be prevented with the standard therapy described in Treatment of Manifestations.Prevention of Secondary ComplicationsAnesthesia is a known trigger for cardiac arrhythmia in individuals with Timothy syndrome. Therefore, any surgical intervention must be performed under close cardiac monitoring. Because clinical experience with Timothy syndrome is scarce, all compounds used for general anesthesia should be regarded as potentially dangerous.Prevention of extracardiac complications, including use of appropriate antibiotic prophylaxis/therapy before surgical intervention, must always be considered.SurveillanceSurveillance includes the following:Monitoring serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptomsA complete cardiac evaluation based on the status of each patient Agents/Circumstances to AvoidThe following should be avoided:All drugs reported to prolong QT interval (www.qtdrugs.org)Drugs and dietary practices that could lead to hypoglycemiaEvaluation of Relatives at RiskWith few exceptions, Timothy syndrome occurs in simplex cases (i.e., a single affected individual in the family). Because sibs could be affected in the case of parental mosaicism (see Risk to Family Members, Sibs of a proband), monitoring of cardiac rate and function during pregnancy is appropriate.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationPharmacologic therapies (mexiletine, calcium channel blockers) to shorten ventricular repolarization, to restore one-to-one conduction, and to reduce the risk of arrhythmias are still in an experimental evaluation phase; no data are available to support their routine use in Timothy syndrome.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Timothy Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCACNA1C12p13.33Voltage-dependent L-type calcium channel subunit alpha-1CGene Connection for the Heart - LQT8 (Timothy syndrome) database CACNA1C @ ZAC-GGM CACNA1C homepage - Mendelian genesCACNA1CData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Timothy Syndrome (View All in OMIM) View in own window 114205CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C 601005TIMOTHY SYNDROME; TSMolecular Genetic PathogenesisExcitable cells contain voltage-dependent calcium channels that can dramatically increase cytosolic Ca2+. In heart and brain, the L-type calcium channel CaV1.2 (CACNA1C, α1C, α11.2) mediates this process. Classic Timothy syndrome (Timothy syndrome type 1) results from one mutation in exon 8A; atypical Timothy syndrome (Timothy syndrome type 2) results from mutations in exon 8.The mechanism of arrhythmia is reduced CaV1.2 channel inactivation, leading to maintained depolarizing Ca2+ currents during the plateau phase of the cardiac action potential. There is relatively little outward current during the plateau phase, so even modest changes in inward calcium current lead to significant QT interval prolongation. This prolongation, in turn, leads to increased risk of spontaneous, abnormal secondary depolarizations (so-called “after-depolarizations”), arrhythmia, and sudden death.Table 4. Selected CACNA1C Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1204G>Ap.Gly402SerNM_000719.6 NP_000710.5c.1216G>Ap.Gly406ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal allelic variants. The gene comprises 50 exons.Pathologic allelic variants. In classic Timothy syndrome (type 1), the only mutation observed is p.Gly406Arg, located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I [Splawski et al 2004].In Timothy syndrome type 2, de novo missense mutations were identified in exon 8 of CaV1.2. Of the two reported mutations, one was analogous to that found in exon 8A in classic Timothy syndrome (type 1), p.Gly406Arg. The other mutation was p.Gly402Ser [Splawski et al 2005].Normal gene product. CaV1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. In CaV1.2, transmembrane segment 6 of domain I (D1/S6) can be encoded by two mutually exclusive exons, 8 and 8A. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs.Abnormal gene product. The mutations p.Gly406Arg and p.Gly402Ser cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed after-depolarizations, factors that increase the risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of Timothy syndrome.CaV1.2 exon 8 is highly expressed in heart and brain, consistent with the severe cardiac and cognitive defects associated with the two mutations that occur in exon 8 [Splawski et al 2005].