Clinical characteristics.

The clinical manifestations of CACNA1C-related disorders include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current. Phenotypes can include nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms); nonsyndromic short QT syndrome (QTc <350 ms), with risk of sudden death; Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval; classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without 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; and CACNA1C-related neurodevelopmental disorder, in which the features tend to favor one or more of the following: developmental delay / intellectual disability, hypotonia, epilepsy, and/or ataxia.

Diagnosis/testing.

The diagnosis of a CACNA1C-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in CACNA1C identified by molecular genetic testing.

Management.

Treatment of manifestations: Beta-blockers (nadolol preferred) and mexiletine may be used for prolonged QT interval; pacemaker placement / temporary pacing for bradycardia with 2:1 atrioventricular block; quinidine for short QT syndrome and Brugada syndrome; consideration of catheter ablation for symptomatic Brugada syndrome; implantable cardioverter defibrillator (ICD) as soon as body weight allows for those with tachyarrhythmias; feeding therapy with low threshold for clinical feeding evaluation and/or radiographic swallowing study for dysphagia; consideration of gastrostomy tube placement for persistent feeding issues; standard treatment for congenital heart defects, developmental delay / intellectual disability, epilepsy, ataxia, hypoglycemia, recurrent infections, and syndactyly.

Prevention of primary manifestations: Arrhythmias must be prevented with the standard therapy, which may include medications, placement of an ICD, and/or ablation. Any surgical intervention must be performed under close cardiac monitoring, as anesthesia is a known trigger for cardiac arrhythmia in individuals with a CACNA1C-related disorder; fever can also be a trigger for arrhythmias in individuals with CACNA1C-related Brugada syndrome and requires aggressive treatment with standard antipyretic drugs.

Surveillance: At each visit, measure growth parameters and evaluate nutritional safety of oral intake; assess mobility and self-help skills; monitor developmental progress and educational needs; assess for behavioral issues; assess for new manifestations such as seizures, changes in tone, and movement disorders; monitor for signs/symptoms of hypoglycemia; and monitor for recurrent infections. Every 6-12 months, follow-up evaluations with a cardiologist to include EKG, Holter, & echocardiogram; monitor those with seizures as clinically indicated. Every 12 months, if remote device monitoring is available: evaluate persons with a pacemaker or ICD.

Agents/circumstances to avoid: All drugs reported to prolong QT interval (see CredibleMeds^®); drugs and dietary practices that could lead to hypoglycemia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation, institution of measures to prevent cardiac arrhythmias, and awareness of agents/circumstances to avoid. Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward. While predictive genetic testing can be used to identify relatives who are heterozygous for a familial CACNA1C pathogenic variant and at risk for CACNA1C-related cardiac arrhythmias, it cannot be used to predict disease course (i.e., whether CACNA1C-related EKG changes and symptoms will occur and, if so, the age of onset and severity).

Pregnancy management: Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans. Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects. Fetuses at risk of being affected with a CACNA1C-related disorder should be monitored for bradycardia and heart rate abnormalities that can be a sign of fetal arrhythmias.

Genetic counseling.

CACNA1C-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CACNA1C-related disorder – particularly those individuals with a syndromic CACNA1C-related disorder (Timothy syndrome or CACNA1C-related neurodevelopmental syndrome) – have the disorder as the result of a de novo pathogenic variant. Some individuals diagnosed with a CACNA1C-related disorder inherited the CACNA1C pathogenic variant from a heterozygous or mosaic parent. If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the proband has a known CACNA1C pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism. Once the CACNA1C pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk for a CACNA1C-related disorder are possible.

Suggestive Findings

CACNA1C-related disorders should be considered in individuals with any of the following clinical and electrocardiographic findings and family history.

Clinical findings

• Cardiovascular malformations such as ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy
• 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
• Isolated neurologic manifestations, including:
  • Mild intellectual disability
  • Apraxia (constructional, dressing, and orobuccal)
  • Hypotonia
  • Poor balance or coordination
• Autism spectrum disorder
• Epilepsy, including generalized and/or focal seizures
• Nonspecific dysmorphic facial features (See Clinical Description.)

Electrocardiographic findings

• A prolonged QT interval on electrocardiogram (EKG) (rate-corrected QT [QTc] interval >480 ms)
• ST segment elevation in right precordial leads (V1-V2) diagnostic for Brugada syndrome (type 1 EKG) associated with a short QT interval
• Short QT interval (QTc <350 ms) and risk of sudden death

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). There may be a history of syncope, aborted cardiac arrest, or sudden death in a child or young adult relative in whom a diagnosis was not recognized. The absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a CACNA1C-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CACNA1C identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous CACNA1C variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with cardiac or neurologic findings are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The first CACNA1C-related disorder was referred to as Timothy syndrome [Splawski et al 2004], a condition with very high mortality with only a few individuals who reached reproductive age. Timothy syndrome consisted of the combination of prolonged QT interval, autism, and congenital heart defect with syndactyly of the fingers and toes; all these individuals had the same pathogenic variant, while a similar phenotype but without syndactyly was subsequently identified in association with comparable but distinct pathogenic variants (see Genotype-Phenotype Correlations).

With the increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders have been recognized. Because CACNA1C is expressed at high levels both in the heart and in the central nervous system, pathogenic variants in CACNA1C can be associated with cardiac and/or neurologic manifestations. Review of the literature specifically focusing on the neurologic involvement in individuals with pathogenic variants in CACNA1C showed that intellectual disability is the most frequent phenotype (89%), followed by hypotonia (55.5%) ataxia (52%), seizures (37.9%), and autism (29%).

Therefore, the clinical manifestations include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current (see Table 2 and Genotype-Phenotype Correlations):

• Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly
• CACNA1C-related neurodevelopmental disorder, in which the features tend to favor one or more of the following: developmental delay / intellectual disability, hypotonia, epilepsy, and/or ataxia
  Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals [Rodan et al 2021].
• Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms)
• Short QT syndrome (QTc <350 ms), with risk of sudden death [Raschwitz et al 2020]
• Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval

The clinical phenotype associated with large deletions/duplications is less defined, as few individuals with this phenotype have been reported (see Table 1).

Electrocardiographic manifestations vary by type of pathogenic variant present in an individual (see Genotype-Phenotype Correlations) but may include long QT interval, short QT interval, and other rhythm disturbances. Individuals with QT prolongation only (no other syndromic features) or individuals with Brugada syndrome or short QT syndrome generally have less severe EKG abnormalities and lower incidence of cardiac events than those who have other syndromic features.

• Long QT interval is defined as a QTc interval >480 ms on EKG and may be associated with the following:
  • Bradycardia or a lower-than-normal heart rate, which frequently, but not always, is observed prenatally or at birth in individuals with markedly increased QT prolongation that causes intermittent 2:1 atrioventricular (AV) block.
    Occasionally, the diagnosis of a CACNA1C-related disorder is suspected prenatally because of fetal distress secondary to cardiac findings of bradycardia with a heart rate that is usually 70-80 (normal fetal heart rate is 120-150) or 2:1 AV block.
  • 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
  • Tachyarrhythmia / sudden death, including ventricular tachycardia and ventricular fibrillation. Arrhythmias are more often polymorphic ventricular tachycardia and torsade de pointes that may degenerate and lead to cardiac arrest. Syncope may occur due to self-limiting ventricular tachycardia.
• Short QT syndrome is defined as a QTc interval <350 due to a reduction of the duration of cardiac action potential. A QTc <350 ms is a hallmark of increased risk of sudden death [Mazzanti et al 2017]. No specific trigger for arrhythmic events has been identified.
• Brugada syndrome manifests clinically with the typical EKG pattern of ST elevation in V1 and V2 leads. Arrhythmic events and sudden death typically occur at rest or during sleep.

Congenital heart defects are reported to include ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy. Biventricular hypertrophy and biventricular dysfunction have been observed on a fetal echocardiogram [Splawski et al 2005]. Although not technically malformations, patent ductus arteriosus and patent foramen ovale have also been reported in affected individuals.

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.

Developmental delay (DD) and intellectual disability (ID). Developmental delays observed include language, motor, and generalized cognitive delay, most often in the mild range, although systematic studies are lacking.

• Affected children have been reported to be impaired in all areas of adaptive function, including communication, socialization, and daily living skills.
• Verbal disabilities are poorly characterized but the few cases described show a large degree of variability, including some affected individuals who are completely nonverbal.
• Some reported children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language [Rodan et al 2021, Cipriano et al 2024].

Other neurodevelopmental features

• Hypotonia
• Ataxia
• Feeding issues. Individuals with the Timothy syndrome phenotype can have feeding issues that may require feeding therapy, thickened feeds, or (in severe cases) a nasogastric or gastrostomy tube placement (see Management).
• Apraxia, which may be constructional, dressing, and/or orobuccal

Epilepsy, including generalized and focal seizures, have been reported [Bozarth et al 2018, Rodan et al 2021]. Further characterization may include:

• Staring followed by syncope
• Focal seizures with eye blinking and facial twitching
• Daily tonic seizures
• Late-onset partial epilepsy
• Epileptic encephalopathy, including severe epileptic encephalopathy during infancy

Neurobehavioral/psychiatric manifestations. Autism spectrum disorder has been reported in some affected individuals and can be present in association with either long or short QT interval [Endres et al 2020]. About 20%-30% of affected individuals have aggressive or destructive behaviors [Timothy et al 2024]. Pathogenic variants in CACNA1C have also been associated with signs and symptoms of major depression, bipolar disorder, and schizophrenia [Cipriano et al 2024].

Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific. Reported features have included [Cipriano et al 2024]:

• Baldness at birth and for the first two years of life, followed by thin scalp hair
• Round face
• Depressed nasal bridge
• Premaxillary underdevelopment
• Low-set ears
• Thin vermilion of the upper lip
• Small, widely spaced teeth and poor dental enamel with severe caries
• Gingival hyperplasia

Other associated findings

• Frequent infections (sinus, ear, respiratory). Two individuals with "common variable immunodeficiency" (CVID) and CACNA1C pathogenic variants have been reported [Bonilla et al 2016, Rodan et al 2021].
• Intermittent hypoglycemia [Dufendach et al 2018] has been rarely reported but is episodic in nature. It does not typically require chronic treatment. There are no formal studies on this particular finding in affected individuals.

Prognosis. The most common cause of death of individuals with Timothy syndrome and nonsyndromic CACNA1C-related disorders is ventricular fibrillation leading to sudden cardiac death, occurring in 60%-80% of affected individuals. Among the CACNA1C-related disorders, the typical Timothy syndrome phenotype has high mortality, and most individuals with this phenotype do not reach reproductive age despite appropriate use of an implantable cardioverter defibrillator and other therapies for non-cardiac conditions. On the other hand, the nonsyndromic QT prolongation, Brugada syndrome, or short QT syndrome phenotypes may be compatible with normal life span if properly diagnosed and treated.

The long-term outcome of individuals with neurologic involvement without apparent cardiac manifestations is poorly characterized. Disabilities (verbal, language, hypotonia, and balance/coordination) are descried in adulthood but the evolution (worsening or improvement) at follow up is not known [Napolitano et al 2021].

Genotype-Phenotype Correlations

Pathogenic variants that induce a gain of function at the cellular level (i.e., increased calcium current) are more likely to lead to:

• The following electrophysiologic findings:
  • Long QTc
  • Bradycardia
  • 2:1 AV block
  • Macroscopic T-wave alternans
  • Tacchyarrythmia / sudden death
• Congenital heart defects
• Cutaneous syndactyly
• Typical facial features
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Seizures
• Recurrent infections

Note: All reported CACNA1C pathogenic variants associated with QT prolongation (with or without syndromic features) occur in the intracellular portion of the protein.

Pathogenic variants that cause a loss of function at the cellular level (i.e., reduced calcium current) are more likely to lead to:

• Short QT syndrome
• Brugada syndrome
• Sudden death

Pathogenic variants that lead to a specific clinical phenotype

• p.Gly406Arg. The classic Timothy syndrome phenotype results from this pathogenic variant in exon 8A, an exon contained in a specific splice variant of CACNA1C (see Molecular Genetics).
• p.Gly402Ser and p.Gly406Arg. The Timothy syndrome phenotype without syndactyly (also referred to in the literature as atypical Timothy syndrome) has been associated with these two pathogenic variants in exon 8 of a CACNA1C alternate splice form.

Deletions/duplications. Preliminary evidence suggests that intragenic deletions/duplications are associated with neurologic disorders with no cardiac phenotype [Rodan et al 2021].

Penetrance

The penetrance of pathogenic variants associated with typical Timothy syndrome is 100% [Splawski et al 2005]. Nonsyndromic forms of CACNA1C-related disorders have lower penetrance that can be estimated in the range of 60%-80% on the basis of published literature [Fukuyama et al 2014, Wemhöner et al 2015].

Nomenclature

The term "Timothy syndrome" (also referred to as Timothy syndrome type 1) was named for Katherine Timothy, who followed children with that phenotype 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.

"Atypical Timothy syndrome" (formerly referred to as Timothy syndrome type 2) was the term used to describe individuals who had QT interval prolongation without syndactyly.

"LQT8" is used in medical literature to refer to both Timothy syndrome and nonsyndromic CACNA1C-related long QT syndrome.

"BRGDA3" refers to CACNA1C-related Brugada syndrome.

"SQT6" refers to CACNA1C-related short QT syndrome [Templin et al 2011].

Prevalence

Timothy syndrome is a very rare condition, probably because of its very high mortality. Approximately 100 cases have been described worldwide. A recent United States survey using a questionnaire sent to families of individuals with the Timothy syndrome phenotype identified 105 people; the majority of identified affected individuals have the p.Gly406Arg pathogenic variant in exon 8A (see Table 7) [Timothy et al 2024].

The prevalence of nonsyndromic CACNA1C-related disorders (long QT syndrome, Brugada syndrome, and short QT syndrome) is not known. Indirect evidence based on genomic sequencing data and available in vitro expression data suggest a prevalence of around 1:10,000 or lower [C Napolitano & SG Priori, personal observations].

Genetic Disorders in the Differential Diagnosis of CACNA1C-Related Cardiac Arrythmias

Long QT syndrome (LQTS). Ten genes (including CACNA1C) are known to be associated with LQTS – of these, KCNH2, KCNQ1, and SCN5A are the most common (see ClinGen Long QT Syndrome Gene Curation Expert Panel) [Wilde et al 2022]. Molecular genetic testing identifies a genetic cause in ~80% of individuals with LQTS, most often in genes associated with autosomal dominant LQTS.

• Nonsyndromic autosomal dominant LQTS is characterized by QT interval prolongation and the absence of non-cardiac features. The clinical phenotype of an individual with CACNA1C-related nonsyndromic LQTS can be indistinguishable from other forms of LQTS. Of note, the macroscopic T-wave alternans EKG pattern seen in those with CACNA1C-related disorders may also be observed in individuals with SCN5A-related LQTS.
• LQTS with extracardiac findings. See Table 3.

Note: Acquired causes of QT prolongation such as electrolyte imbalance (e.g., hypokalemia) or QT-prolonging drugs (e.g., macrolide antibiotics) should be excluded before considering the diagnosis of a CACNA1C-related disorder. In such cases the removal of the offending agent should lead to EKG normalization. However, some individuals with drug-induced QT prolongation may also have a genetic predisposition (including pathogenic variants in LQTS-related genes).

Short QT syndrome. Heterozygous pathogenic variants in KCNH2, KCNJ2, KCNQ1, and SLC4A3 are known to be associated with short QT syndrome (see ClinGen Short QT Syndrome Gene Curation Expert Panel and OMIM PS609620).

Brugada syndrome. Forty-two genes have been associated with Brugada syndrome; however, SCN5A is the only gene classified as definitively associated with Brugada syndrome by the ClinGen Brugada Syndrome Gene Curation Expert Panel (see also Wilde et al [2022] and Pannone et al [2024]). Pathogenic variants in SCN5A account for 30% of Brugada syndrome. Pathogenic variants in other Brugada syndrome-related genes are identified in less than 1% of affected individuals.

Genetic Disorders in the Differential Diagnosis of CACNA1C-Related Neurodevelopmental Syndrome

The phenotypic features associated with CACNA1C-related neurodevelopmental syndrome are not sufficient to diagnose this condition clinically; all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series for genes associated with:

• Autosomal dominant intellectual developmental disorders;
• Autosomal recessive intellectual developmental disorders;
• Syndromic X-linked intellectual developmental disorders.

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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CACNA1C-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Standard care is recommended for cardiovascular malformations, surgical release of syndactyly, and hypoglycemia.

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

Prevention of Primary Manifestations

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

Anesthesia is a known trigger for cardiac arrhythmia in individuals with a CACNA1C-related disorder. Therefore, any surgical intervention must be performed under close cardiac monitoring. Because clinical experience with CACNA1C-related disorders is scarce, all compounds used for general anesthesia should be regarded as potentially dangerous.

Fever can be a trigger for arrhythmias in individuals with CACNA1C-related Brugada syndrome (as in Brugada syndrome in general) and requires aggressive treatment with standard antipyretic drugs.

Surveillance

Agents/Circumstances to Avoid

The following should be avoided:

• All drugs reported to prolong QT interval (See CredibleMeds^®.)
• Drugs and dietary practices that could lead to hypoglycemia

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation, institution of measures to prevent cardiac arrhythmias, and awareness of agents/circumstances to avoid. Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward. Parents of a proband should be screened whenever possible for the known familial pathogenic variant in genomic DNA from peripheral blood lymphocytes or saliva/buccal tissue.

Note: Predictive genetic testing can be used to identify relatives who are heterozygous for a familial CACNA1C pathogenic variant and at risk for CACNA1C-related cardiac arrhythmias but cannot be used to predict disease course (i.e., whether CACNA1C-related EKG changes and symptoms will occur and, if so, the age of onset and severity).

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Pregnancy Management

• Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans.
• Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects.
• Fetuses at risk of being affected with a CACNA1C-related disorder should be monitored for bradycardia and heart rate abnormalities that can be a sign of fetal arrhythmias. Fetal bradycardia is observed in 43% of pregnancies [Timothy et al 2024].

See MotherToBaby for further information on medication use during pregnancy.

Mode of Inheritance

CACNA1C-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with a CACNA1C-related disorder – particularly those individuals with a syndromic CACNA1C-related disorder (Timothy syndrome or CACNA1C-related neurodevelopmental syndrome) – have the disorder as the result of a de novo pathogenic variant.
• Some individuals diagnosed with a CACNA1C-related disorder inherited the CACNA1C pathogenic variant from a heterozygous or mosaic parent. Due to reduced penetrance, a parent who is heterozygous for a CACNA1C pathogenic variant may or may not have LQTS-related EKG changes and symptoms. (Note: Detailed EKG evaluation including exercise EKG is often necessary to identify affected family members accurately.)
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and clarify their need for cardiac evaluation and institution of measures to prevent cardiac arrhythmias (all individuals with a CACNA1C pathogenic variant are at risk for cardiac arrhythmia [see Clinical Description]). Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a CACNA1C pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the CACNA1C pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Splawski et al 2004].* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a CACNA1C pathogenic variant may be mildly/minimally affected [Etheridge et al 2011].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the CACNA1C pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Heterozygous sibs are at risk for cardiac arrhythmias and other possible manifestations of CACNA1C-related disorder and should undergo detailed clinical evaluation (see Table 4) and surveillance (see Table 6).
• If the CACNA1C pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism. Parental mosaicism has been reported [Splawski et al 2004, Etheridge et al 2011].
• If the parents of a proband are clinically unaffected and do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting a CACNA1C pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms.

Offspring of a proband. Each child of an individual with a CACNA1C-related disorder has a 50% chance of inheriting the CACNA1C pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CACNA1C pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Specific risk issues. With the reduced penetrance of cardiac arrhythmia in individuals with a CACNA1-related disorder, careful EKG evaluation including exercise EKG is often necessary to identify affected family members accurately. The absence of a family history of sudden death is common and does not negate the diagnosis or preclude the possibility of sudden death in relatives.

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/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the CACNA1C pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Fetal echocardiography. Monitoring of cardiac rate and function during pregnancy is appropriate.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CACNA1C encodes voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C), which is involved in the embryologic development of several organs and processes including the central nervous system [Panagiotakos et al 2019], the bones [Ramachandran et al 2013, Atsuta et al 2019], and glucose metabolism [Pan et al 2016]. Voltage-dependent calcium channels (also called CaV1.2) are involved in the control of the duration of electrical activation (action potential duration) in neuronal cells, which is the counterpart of the QT interval in the myocardium. In cardiac cells, calcium entry triggers the release of more calcium from the sarcoplasmic reticulum, leading to the contraction of muscle fibers. The role of the calcium current in the nervous system is less well defined.

Most gain-of-function pathogenic variants in CACNA1C impair Ca_V1.2 channel inactivation, leading to maintained depolarizing Ca²⁺ current [Napolitano & Antzelevitch 2011]. Other pathogenic variants increase the current density [Napolitano & Antzelevitch 2011]. There is relatively little outward current during the plateau phase due to high membrane impedance, 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 afterdepolarizations), arrhythmia, and sudden death.

Loss-of-function pathogenic variants in CACNA1C have an opposite mechanism, with reduced current density that shortens the duration of electrical activation in myocardial cells [Napolitano & Antzelevitch 2011]. Therefore, shortening of the QT interval is the direct consequence of this type of change. The pathogenesis of ST segment elevation leading to a Brugada syndrome phenotype is less clear due to lack of experimental models.

CACNA1C 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 tissue-specific regulation [Napolitano & Antzelevitch 2011]. This may explain the variability of the clinical phenotypes associated with pathogenic variants occurring in alternatively spliced exons or in different regions of the protein.

Mechanism of disease causation. See Table 7.

CACNA1C-specific laboratory technical considerations. Due to the possibility of alternative splicing and several possible transcripts, sequencing the entire genomic region of CACNA1C is required for a thorough molecular analysis.

Author Notes

Carlo Napolitano is a senior investigator currently in Molecular Cardiology at the IRCCS Maugeri Scientific Institutes and the Department of Molecular Medicine at the University of Pavia. He has more than 400 publications with 20,000 citations in the field of the genetic basis of cardiac arrhythmias, cardiac electrophysiology, and sudden death (orcid.org/0000-0002-7643-4628).

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.

Author History

Raffaella Bloise, MD (2006-2024)
Carlo Napolitano, MD, PhD (2006-present)
Silvia G Priori, MD, PhD (2006-present)
Igor Splawski, PhD; Harvard Medical School (2006-2021)
Katherine W Timothy, BS (2006-2024)

Revision History

• 18 September 2025 (ma) Revision: involvement of non-SCN5A genes in Brugada syndrome
• 19 December 2024 (ma) Comprehensive update posted live
• 11 February 2021 (ha) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 29 July 2008 (me) Comprehensive update posted live
• 15 February 2006 (me) Review posted live
• 5 July 2005 (is) Original submission

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