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Timothy Syndrome

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

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

Author Information
, 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, 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
, MD, PhD
Department of Molecular Cardiology
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy
, MD
Department of Molecular Cardiology
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy

Initial Posting: ; Last Update: April 21, 2011.

Summary

Disease characteristics. Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. The two forms are type 1 (classic) and type 2, a rare form caused by mutation in a transcript variant of the same gene. Cardiac findings include a rate-corrected QT interval of between 480 ms and 700 ms and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). 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 flat nasal bridge, low-set ears, thin 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 one of three known mutations in CACNA1C, the gene encoding the CaV1.2 calcium channel.

Management. Treatment of manifestations: Treatment includes use of beta-blockers 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, because these drugs 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 a 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. Timothy syndrome types 1 and 2 are inherited in an autosomal dominant manner. Timothy syndrome usually results from a de novo mutation. 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 mutation. Prenatal testing is possible for pregnancies at increased risk in families in which the disease-causing mutation has been identified.

GeneReview Scope

Timothy Syndrome: Included Disorders
  • Timothy syndrome type 1
  • Timothy syndrome type 2

Diagnosis

Clinical Diagnosis

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).

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

The 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 Testing

Gene. CACNA1C, the gene encoding the CaV1.2 calcium channel, is the only gene in which mutation is known to cause Timothy syndrome [Splawski et al 2004, 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 2

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency 3
Type 1Type 2
CACNA1CTargeted mutation analysisp.Gly406Arg (exon 8A)100%NA
p.Gly406Arg (exon 8)NAUnknown 2
p.Gly402Ser (exon 8)NAUnknown 2
Sequence analysisSequence variants 3100%Unknown
Deletion/duplication analysis 4Exonic, multiexonic, and whole-gene deletions/duplicationsUnknown; none reported 5Unknown; none reported

NA = not applicable

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

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. One of two individuals tested to date

5. 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. For issues to consider in interpretation of sequence analysis results, click here.

6. 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.

7. 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.)

Testing Strategy

To confirm/establish the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Timothy Syndrome Type 1

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; 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 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, 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
  • Flat nasal bridge
  • Small upper jaw
  • Baldness at birth and for the first two years of life, followed by thin scalp hair
  • Small, 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 findings

  • Frequent infections (sinus, ear, respiratory) secondary to altered immune responses
  • Intermittent hypoglycemia

Table 3. Extracardiac Phenotype of Classic Timothy Syndrome

Extracardiac PhenotypeAffected 1/Evaluated%Not Available
Cutaneous syndactyly25/251000
Craniofacial findings 218/21854
Sepsis or severe infections11/19576
Neuropsychiatric involvement15/19786
Autism (FE)3/103015
Autism spectrum disorder (FE)2/102015
Severe language delay (FE)1/101015
Problems in social relationships + mild language delay (FE)2/102015

FE= 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 teeth

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; 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 2

Reported 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.

Genotype-Phenotype Correlations

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.

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).

Penetrance

Penetrance is 100% in the 18 affected individuals with Timothy syndrome type 1 reported to date [Splawski et al 2004, Splawski et al 2005, Njoe et al 2005].

Anticipation

Anticipation is not observed.

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 mutation is causative.

Prevalence

Only 20 individuals with molecularly confirmed Timothy syndrome type 1 and two with type 2 have been reported to date [Splawski et al 2004, Njoe et al 2005, Splawski et al 2005].

Differential Diagnosis

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.

  • 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 mutation 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 mutation 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 mutation.
  • 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 mutation 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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

  • Electrocardiogram
  • Echocardiogram
  • Developmental assessment
  • Dysmorphology evaluation

Treatment of Manifestations

Long QT interval

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

With 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 Investigation

Pharmacologic 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.

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 a de novo mutation.

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 mutation, 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 mutation include molecular genetic testing of several tissues, including sperm, for the disease-causing CACNA1C mutation 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 familial disease-causing mutation 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 mutation, 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 mutation.

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 a 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

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation 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
  • 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 #20
    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. 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 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1204G>Ap.Gly402SerNM_000719​.6
NP_000710​.5
c.1216G>Ap.Gly406Arg

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.

Gene structure. The gene comprises 50 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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].

References

Literature Cited

  1. Njoe SM, Wilde AA, van Erven L, Blom NA. Syndactyly and long QT syndrome (CaV1.2 missense mutation G640R) is associated with hypertrophic cardiomyopathy. Heart Rhythm. 2005;2:1365–8. [PubMed: 16360093]
  2. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995a;76:744–5. [PubMed: 7572644]
  3. 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]
  4. 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]
  5. 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 USA. 2005;102:8089–96. [PMC free article: PMC1149428] [PubMed: 15863612]
  6. 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]

Suggested Reading

  1. Ruan Y, Bloise R, Napolitano C, Priori SG. L-type calcium channel disease. In: Gussak I, Antzelevitch C, eds. Electrical Diseases of the Heart. Genetics, Mechanisms, Treatment, Prevention. London, UK: Springer-Verlag; 2008:187-93.
  2. 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]
  3. 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]
  4. 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. 2008;587:551–65. [PMC free article: PMC2670080] [PubMed: 19074970]
  5. 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

  • 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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