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Timothy Syndrome

Synonym: Long QT Syndrome with Syndactyly, Long QT Syndrome Type 8

, MD, PhD, , PhD, , BS, , MD, and , MD, PhD.

Author Information
, MD, PhD
Department of Molecular Cardiology
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy
Langone Medical Center
New York University
New York, New York
, PhD
Assistant Professor, Harvard Medical School
Assistant, Children’s Hospital Boston
Boston, Massachusetts
, BS
Clinical Coordinator (retired), Children's Hospital Boston
Harvard Medical School
Boston, Massachusetts
, MD
Department of Molecular Cardiology
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy
, MD, PhD
Professor, Department of Cardiology
University of Pavia
Department of Molecular Cardiology
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy
Langone Medical Center
New York University
New York, New York

Initial Posting: ; Last Update: July 16, 2015.

Summary

Clinical characteristics.

Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.

Diagnosis/testing.

Timothy syndrome is diagnosed by clinical features and by the presence of a pathogenic variant in CACNA1C, the gene encoding the CaV1.2 calcium channel.

Management.

Treatment of manifestations: Treatment includes use of beta-blockers and/or other antiarrhythmic drugs to maintain QT interval stability to prevent ventricular tachyarrhythmia. In some instances pacemakers can be placed during the first days of life to control 2:1 AV block and resultant bradycardia, but an implantable cardioverter defibrillator to prevent sudden cardiac death should be considered in all affected persons. Treatment for congenital heart defects follows usual protocols.

Prevention of secondary complications: Because anesthesia is a known trigger for cardiac arrhythmia, close cardiac monitoring is warranted during surgery.

Surveillance: Monitoring of serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptoms.

Agents/circumstances to avoid: Drugs reported to prolong QT interval; drugs and dietary practices that could lead to hypoglycemia.

Evaluation of relatives at risk: Although Timothy syndrome usually occurs as a result of de novo mutation, in rare instances sibs could be affected because of parental germline mosaicism; thus, monitoring of fetal cardiac rate and function during at-risk pregnancies is warranted.

Genetic counseling.

Due to high mortality Timothy syndrome often results from a de novo pathogenic variant. The risk to sibs of a proband is small; however, because parental germline mosaicism occurs, the sibs of a proband may be at increased risk of inheriting a CACNA1C pathogenic variant. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.

Diagnosis

Timothy syndrome is a multisystem disorder characterized by cardiac, hand, facial, and neurodevelopmental features caused by pathogenic variants in the CaV1.2 L-type calcium channel gene, CACNA1C.

Suggestive Findings

Diagnosis of Timothy syndrome should be suspected in individuals with the following two features:

  • A rate-corrected QT (QTc) interval >480 ms
  • Unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three

Additional 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 depressed nasal bridge, low-set ears, thin vermilion of the upper lip, round face (in ~85% of individuals)
  • Neurologic symptoms including autism, seizures, intellectual disability, hypotonia

Establishing the Diagnosis

The diagnosis of Timothy syndrome is established in a proband with the identification of a pathogenic variant in CACNA1C (see Table 1).

Molecular testing approaches may include the following:

Table 1.

Molecular Genetic Testing Used in Timothy Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CACNA1CTargeted analysis for pathogenic variants>95% 3
Sequence analysis 4100% 5
Gene-targeted deletion/duplication analysis 6Unknown; none reported 7
1.

See Table A. Genes and Databases for chromosome locus and protein name.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

All 16 individuals with classic Timothy syndrome in whom molecular genetic testing was performed had the same pathogenic variant, p.Gly406Arg, in exon 8A of CACNA1C [Splawski et al 2004].

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gillis et al [2012] reported a pathogenic variant in exon 38.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No deletions or duplications of CACNA1C have been reported to cause Timothy syndrome. No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Phenotypic features of 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 Manifestations

Long 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 LQTS type 3 (SCN5A pathogenic variant) and marked prolongation of the QT interval.

Age at diagnosis. 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

Cardiac PhenotypeAffected 1/Evaluated%Not Available
QTc prolongation25/251000
TWA7/107015
Functional 2:1 AV block17/21814
Tachyarrhythmias21/25840
Congenital heart disease
(PDA, PFO, VSD, TOF, HCM)
13/21614

TWA = T-wave alternance

PDA = patent ductus arteriosus

PFO = patent foramen ovale

VSD = ventricular septal defect

TOF = tetralogy of Fallot

HCM = hypertrophic cardiomyopathy

1.

n = 25 (13 males, 12 females)

Extracardiac Manifestations

Cutaneous 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 findings

  • Low-set ears
  • Depressed nasal bridge
  • Premaxillary underdevelopment
  • Baldness at birth and for the first two years of life, followed by thin scalp hair
  • Small, widely spaced 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. Profound developmental delay, intractable seizures, stroke, cortical blindness, and myopathy were reported in one individual [Gillis et al 2012].

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 findings

  • Frequent infections (sinus, ear, respiratory) secondary to altered immune responses
  • Intermittent hypoglycemia
  • Joint contractures [Gillis et al 2012]

Table 3.

Extracardiac Phenotype of Timothy Syndrome

Extracardiac PhenotypeAffected 1/Evaluated%Not Available
Cutaneous syndactyly25/251000
Craniofacial findings 218/21854
Sepsis or severe infections11/19576
Neuropsychiatric involvement15/19786
Autism 33/103015
Autism spectrum disorder 32/102015
Severe language delay 31/101015
Problems in social relationships + mild language delay 32/102015
1.

n = 25: 13 males, 12 females

2.

Low-set ears, depressed nasal bridge, premaxillary underdevelopment, baldness at birth, thin scalp hair, small, widely spaced teeth

3.

Formal evaluation for autism was performed.

Cause 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]. Two deaths reported were not related to tachyarrhythmi: one from severe infections (despite aggressive antibiotic therapy) and the other from complications of intractable hypoglycemia.

Genotype-Phenotype Correlations

The classic Timothy syndrome phenotype results from the p.Gly406Arg pathogenic variant in exon 8A, an exon contained in a specific splice variant of CACNA1C (see Molecular Genetics). Transcripts containing exon 8A are found in approximately 20% of all cardiac mRNAs. Compared to atypical Timothy syndrome (formerly referred to as 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 pathogenic variants (p.Gly402Ser and p.Gly406Arg) in exon 8 of an alternate splice form that represents 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 [Bloise et al 2007].

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 pathogenic variant is present in some, not all, cells).

Gillis et al [2012] reported a de novo (without confirmation of parental identity) novel CACNA1C pathogenic variant (p.Ala1473Gly) associated with a severe phenotype: profound developmental delay, intractable seizures, joint contractures, stroke, cortical blindness, and myopathy.

Penetrance

No study has specifically investigated the issue of the penetrance of TS. Of note, however, penetrance was 100% in the 18 affected individuals with Timothy syndrome reported to date [Splawski et al 2004, Lo-A-Njoe et al 2005, Splawski et al 2005] and it has remained very high (22 of 23 individuals with pathogenic variants had clearly abnormal electrocardiogram) in the two reports of gain-of-function CACN1C pathogenic variants in association with QT prolongation without extracardiac abnormalities [Fukuyama et al 2014, Wemhöner et al 2015].

Nomenclature

Timothy syndrome is named after Katherine Timothy, who followed children with the disorder for more than 14 years, identifying the non-cardiac manifestations and collecting samples that led to the discovery of the gene in which pathogenic variants are causative.

Prevalence

The prevalence of TS in not known. Its high mortality and severe manifestations point to a very low prevalence in the general population. Milder phenotypes of “isolated” QT prolongation associated with pathogenic variants in CACNA1C may have higher prevalence, although it has never been quantified.

Differential Diagnosis

Long QT syndrome (LQTS) 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. LQTS is typically inherited in an autosomal dominant manner.

  • Nonsyndromic autosomal dominant LQTS 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 pathogenic variant in one of the genes associated with LQTS have symptoms; cardiac events may occur from infancy through middle age but are most common from the pre-teen years through the 20s.

    The clinical phenotype of an individual with a CACNA1C pathogenic variant but no extracardiac findings (i.e., LQTS type 8) can be indistinguishable from other forms of LQTS.
  • 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, wide-spaced eyes, 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 pathogenic variant in KCNJ2, which encodes the inward rectifier potassium channel protein, Kir2.1. KCNJ2 pathogenic variants may also cause a purely cardiac 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 pathogenic variants.
  • 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 pathogenic variants cause JLNS are KCNQ1 and KCNE1; mutation of these genes can also cause a purely cardiac phenotype.

    JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are typically heterozygous for a pathogenic variant in KCNQ1 or KCNE1. Rarely, only one parent may be a carrier; and the other pathogenic variant may arise de novo. Parents may or may not have the LQTS phenotype.

Acquired causes of QT prolongation due to electrolyte imbalance (e.g., hypokalemia) or QT-prolonging drugs (e.g., macrolide antibiotics) should be excluded before considering Timothy syndrome diagnosis. In such cases the removal of the offending agent should lead to ECG normalization. However, some cases of drug-induced QT prolongation may also have a genetic predisposition (including pathogenic variants in long QT syndrome genes).

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.

See Long QT syndrome: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Timothy syndrome, the following evaluations are recommended:

  • Electrocardiogram
  • Echocardiogram
  • Developmental and neurologic assessment
  • Orthopedist consulation for skeletal abnormalities
  • Medical genetics consultation

Treatment of Manifestations

Note: All medical procedures requiring anesthesia should be performed with caution (see Prevention of Secondary Complications).

Long QT interval

  • Beta-blockers. While most individuals with Timothy syndrome are treated with beta-blockers to maintain QT interval stability and thereby prevent ventricular tachyarrhythmia, no data concerning the effectiveness of beta-blockers are available. Verapamil and ranolazine have been reported effective in case reports. However, no cohort-based analysis of the efficacy of pharmacologic therapy is 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.
  • Implants. The implantable cardioverter defibrillator is most important in preventing sudden cardiac death in individuals with Timothy syndrome. An 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. The possibility of reduced immune response should be considered.

Surgical release of syndactyly. Standard treatment is indicated.

Prevention of Primary Manifestations

Arrhythmias in Timothy syndrome must be prevented with the standard therapy described in Treatment of Manifestations.

Prevention of Secondary Complications

Anesthesia 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.

Surveillance

Surveillance includes the following:

  • Monitoring of serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptoms
  • A complete cardiac evaluation based on the status of the individual patient

Agents/Circumstances to Avoid

The following should be avoided:

  • All drugs reported to prolong QT interval (www.qtdrugs.org)
  • Drugs and dietary practices that could lead to hypoglycemia

Evaluation of Relatives at Risk

Using molecular genetic testing for the CACNA1C pathogenic variants found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Pharmacologic therapies under investigation to shorten ventricular repolarization, restore one-to-one conduction, and reduce the risk of arrhythmias include sodium channel blockers and calcium channel blockers. Although verapamil has been used in one case [Jacobs et al 2006] and the partial effectiveness of sodium channel blockers mexiletine and ranolazine has been reported for two patients [Shah et al 2012, Gao et al 2013], 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Timothy syndrome is inherited in an autosomal dominant manner. Although Timothy syndrome has been reported to result from parental germline mosaicism, it is usually the result of de novo pathogenic variants of CACNA1C.

Risk to Family Members

Parents of a proband

  • To date, none of the individuals diagnosed with Timothy syndrome has had an affected parent.
  • A proband with Timothy syndrome usually has the disorder as the result of a de novo pathogenic variant, but may have it as the result of parental germline mosaicism.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of several tissues, including sperm, for the CACNA1C pathogenic variant identified in the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • Germline mosaicism has been observed:
    • Two affected sibs had an unaffected mother [Splawski et al 2004].
    • In a family with one affected child, syndactyly was suspected on fetal ultrasound examination in a subsequent pregnancy. Molecular genetic testing of cells obtained by amniocentesis identified the CACNA1C pathogenic variant in the fetus. The pregnancy was interrupted and syndactyly was confirmed [Bloise, unpublished observation].
  • Timothy syndrome typically occurs as the result of a de novo pathogenic variant, and thus the risk to the sibs of a proband is small. However, because parental germline mosaicism occurs [Splawski et al 2004], the sibs of a proband may be at increased risk of inheriting a CACNA1C pathogenic variant.

Offspring of a proband. No individuals with Timothy syndrome have been reported to live long enough to reproduce.

Other family members of a proband. Because Timothy syndrome occurs as a result of either de novo mutation or parental germline mosaicism, family members other than (possibly) the sibs of a proband are not at increased risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the CACNA1C pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Fetal echocardiography. 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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the CACNA1C pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • QTsyndrome.ch
    Email: info@qtsyndrome.ch
  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • Canadian SADS Foundation
    9-6975 Meadowvale Town Centre Circle
    Suite 314
    Mississauga Ontario L5N 2V7
    Canada
    Phone: 877-525-5995 (toll-free); 905-826-6303
    Fax: 905-826-9068
    Email: info@sads.ca
  • Heart of Pediatric Electrophysiology (HOPE)
    5 Pine Drive
    Park Ridge NJ 07656
    Phone: 201-505-1909
    Fax: 201-505-1909
    Email: chrisbadame@msn.com
  • SADS UK
    Churchill House
    Horndon Industrial Park
    Suite 6
    West Horndon Essex CM13 3XD
    United Kingdom
    Phone: 01277 811215
    Email: sadsuk@btconnect.com
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #202
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • Long QT Syndrome (LQTS) Registry
    An ongoing research study with the goal of contributing to a better understanding of the genetics, natural history, and treatment of LQTS. Currently enrolling families in which a mutation has already been identified.
    University of Rochester Medical Center
    265 Crittenden Boulevard
    CU 420653
    Rochester NY 14642-0653
    Phone: 585-276-0016
    Fax: 585-273-5283

Molecular Genetics

Information 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 Databases

Data 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)

114205CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
601005TIMOTHY SYNDROME; TS

Molecular Genetic Pathogenesis

Excitable 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.

Gene structure. CACNA1C comprises 50 exons and spans approximately 700 kb on the human chromosome 12; it has a complex genomic structure that undergoes extensive alternative splicing producing at least 36 different transcripts. Alternative splicing is regulated by a number of different factors including a tissue-specific regulation [Napolitano & Antzelevitch 2011]. This may explain the variability of the clinical phenotypes associated with mutations occurring in alternatively splices exons or in different regions of the protein. For a detailed summary of gene and protein information, see Table A.

Pathogenic allelic variants. In Timothy syndrome, the original pathogenic variant observed was p.Gly406Arg, located in alternatively spliced exon 8A (reference sequence NM_0007129.6), encoding transmembrane segment S6 of domain I [Splawski et al 2004].

In atypical Timothy syndrome (type 2), de novo missense pathogenic variants were identified in exon 8 of an CACNA1C alternate splice form (reference sequence NM_001167625.2). Of the two reported pathogenic variants, one was analogous to that found in exon 8A in classic Timothy syndrome (type 1), p.Gly406Arg. The other pathogenic variant was p.Gly402Ser [Splawski et al 2005].

The pathogenic variants in exon 8 and 8A of the CACNA1C alternate splice forms are located in the terminal part of transmembrane segment 6 in domain I of the predicted protein topology. The p.Ala1473Gly variant identified by Gillis et al [2012] is located at the end of transmembrane segment 6 in domain IV. Other CACNA1C pathogenic variants identified in cases of QT interval prolongation in the absence of other typical TS phenotypes are p.Arg858His and p.Ala582Asp [Fukuyama et al 2014]. Residue 856 is located in the intracellular loop between domains II and III; 582 is in the loop between segments 2 and 3 of domain II. Overall, it appears that all gain-of-function variants identified in CACAN1C are located in the intracellular side of the protein.

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 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1204G>Ap.Gly402SerNM_000719​.6 1
NP_000710​.5
c.1216G>Ap.Gly406Arg
c.4418C>Gp.Ala1473Gly
c.1216G>Ap.Gly406ArgNM_001167625​.1 2
NP_001161097​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Contains exon 8A

2.

Contains exon 8

Normal gene product. CACNA1C encodes CaV1.2, the cardiac L-type calcium channel, which 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 pathogenic variants 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 variants of CaV1.2 exons 8 and 8A cause distinct forms of Timothy syndrome.

CaV1.2 with exon 8 is highly expressed in heart and brain, consistent with the severe cardiac and cognitive defects associated with the two pathogenic variants that occur in exon 8 [Splawski et al 2005].

References

Literature Cited

  1. Bloise R, Napolitano C, Timothy KW, Pontes Cavalcanti D, Szepesvary E, Drago F, Nastoli J, Splawski I, Keating MT, Priori SG. Clinical profile and risk of sudden death in children with Timothy syndrome. Circulation. 2007;114 suppl II:502.
  2. Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace. 2014;16:1828–37. [PubMed: 24728418]
  3. Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H, Li L, Timothy KW, Zhang L, Li C, Yan GX. Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. Circ Arrhythm Electrophysiol. 2013;6:614–22. [PubMed: 23580742]
  4. Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L, Babul-Hirji R, Chitayat D. Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. Am J Med Genet A. 2012;158A:182–7. [PMC free article: PMC3319791] [PubMed: 22106044]
  5. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP. Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet A. 2015;167A:629–34. [PubMed: 25691416]
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  8. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995a;76:744–5. [PubMed: 7572644]
  9. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995b;25:59–64. [PubMed: 7798527]
  10. Napolitano C, Antzelevitch C. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel. Circ Res. 2011;108:607–18. [PMC free article: PMC3056572] [PubMed: 21372292]
  11. Reichenbach H, Meister EM, Theile H. The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet. Kinderarztl Prax. 1992;60:54–6. [PubMed: 1318983]
  12. Shah DP, Baez-Escudero JL, Weisberg IL, Beshai JF, Burke MC. Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8). Pacing Clin Electrophysiol. 2012;35:e62–4. [PubMed: 20883512]
  13. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005;102:8089–96. [PMC free article: PMC1149428] [PubMed: 15863612]
  14. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31. [PubMed: 15454078]
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Suggested Reading

  1. Sung RJ, Wu YH, Lai NH, Teng CH, Luo CH, Tien HC, Lo CP, Wu SN. Beta-adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study. Am J Physiol Heart Circ Physiol. 2010;298:H33–44. [PubMed: 19855067]
  2. Thiel WH, Chen B, Hund TJ, Koval OM, Purohit A, Song LS, Mohler PJ, Anderson ME. Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation. 2008;118:2225–34. [PMC free article: PMC3226825] [PubMed: 19001023]
  3. Yarotskyy V, Gao G, Peterson BZ, Elmslie KS. The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol. 2009;587:551–65. [PMC free article: PMC2670080] [PubMed: 19074970]
  4. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471:230–4. [PMC free article: PMC3077925] [PubMed: 21307850]

Chapter Notes

Acknowledgments

We are grateful to all of the individuals with Timothy syndrome and their families for donated time and samples. We would also like to thank the physicians who identified and are providing care for individuals with Timothy syndrome.

Revision History

  • 16 July 2015 (me) Comprehensive update posted live
  • 21 April 2011 (me) Comprehensive update posted live
  • 20 August 2009 (cd) Revision: prenatal diagnosis available clinically
  • 27 January 2009 (cd) Revision: sequence analysis available clinically
  • 29 July 2008 (me) Comprehensive update posted live
  • 15 February 2006 (me) Review posted to live Web site
  • 5 July 2005 (is) Original submission
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