Clinical Diagnosis

Timothy syndrome is a multisystem disorder characterized by cardiac, hand, facial, and neurodevelopmental features caused by mutations in the Ca_V1.2 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 Ca_V1.2 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 Ca_V1.2 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 analysis
  • Classic 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 is clinically available; however, the usefulness of such 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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1		Test Availability
			Type 1	Type 2
CACNA1C	Targeted mutation analysis	p.Gly406Arg (exon 8A)	100%	NA	Clinical
		p.Gly406Arg (exon 8)	NA	Unknown 2
		p.Gly402Ser (exon 8)	NA	Unknown 2
	Sequence analysis	Sequence variants 3	100%	Unknown
	Deletion / duplication analysis 4	Exonic, multiexonic, and whole-gene deletions / duplications	Unknown; none reported 5	Unknown; none reported

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

NA = not applicable

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

2. One of two individuals tested to date

3. 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. See CMA.

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 Strategy

To confirm/establish the diagnosis in a proband

• Identification 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in CACNA1C.

Natural History

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, Lo-A-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, Lo-A-Njoe et al 2005, Splawski et al 2005].

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 Ca_V1.2 (CACNA1C, α_1C, 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 Ca_V1.2 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.

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 Ca_V1.2. 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. Ca_V1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. In Ca_V1.2, transmembrane segment 6 of domain I (D1/S6) can be encoded by two mutually exclusive exons, 8 and 8A. The spliced form of Ca_V1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of Ca_V1.2 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 Ca_V1.2 exons 8 and 8A cause distinct forms of Timothy syndrome.

Ca_V1.2 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].

Literature Cited

1. Lo-A-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]

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