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CACNA1C-related disorders

Topic: Medicine

 From HandWiki - Reading time: 21 min

CACNA1C-related disorders (CRDs) are a group of rare genetic conditions caused by genetic variants in the gene CACNA1C[1]. CACNA1C encodes the voltage-gated calcium channel (CaV1.2), widely expressed throughout the body, subsequently causing a wide range of multi-system symptoms.[1] The term CACNA1C-Related Disorders is an umbrella term that includes Timothy syndrome (Online Mendelian Inheritance in Man (OMIM) 601005), CACNA1C-Related Disorder (Online Mendelian Inheritance in Man (OMIM) 620029)[lower-alpha 1] and single organ system presentations, such as Long QT Type 8 (Online Mendelian Inheritance in Man (OMIM) 618447) (Figure 1).[2] Individuals with CRDs typically present with multisystem involvement spanning neurological, neurodevelopmental, cardiac, endocrine, gastrointestinal, skeletal and immune dysregulation abnormalities[2] (Figure 1). Severity of CRDs ranges from isolated cardiac arrhythmia to profound multisystem involvement, which can vary between individuals.[2]

Figure 1. Euler diagram of diagnoses and syndromes featuring CACNA1C gene variants[2]. CC BY-SA 4.0 License.

Classification

There are three diagnostic categories that rare pathogenic CACNA1C variants cause: Timothy Syndrome, the newly coined CACNA1C-Related Disorder (CRD) (OMIM #620029) (Fig 2) and single organ system presentation, such as Long QT Type 8:[2]

Figure 2. Flow chart for syndromic interpretation and diagnosis in individuals with pathogenic CACNA1C rare variants [2]. CC BY-SA 4.0 License.

1. Timothy syndrome, is when an individual with a rare genetic variant in CACNA1C also presents with the classic dyad of prolonged QT interval and a neurodevelopmental disorder (such as developmental delay, intellectual disability, or autism), following appropriate clinical genetic evaluation.

Two Timothy syndrome subtypes are recognised: Type 1 and Type 2.[3] Subtyping Timothy syndrome type 1 and Timothy syndrome type 2 diagnoses should be assigned based on phenotypic syndromic features and not be dependent upon the specific p.G406R variant.[2] Historically, individuals with Type 1 predominantly carry p.G406R in exon 8A, presenting with prolonged QT interval, cardiac arrhythmia and syndactyly and further features of autism, developmental delay, seizures, baldness at birth, characteristic facies (flattened nasal bridge, low-set ears, small upper jaw, thin upper lip), small teeth, hypoglycaemia, hypothermia, and hypotonia.[1] Individuals with Type 2 predominantly harbour p.G406R in exon 8, presenting with a similar phenotype to Type 1 but with hip dysplasia.[4][3]

Individuals with pathogenic CACNA1C variants in utero, presenting with bradycardia, should be suspected as Timothy syndrome individuals who require monitoring and follow-up assessment.[2] In the first year of life, Timothy syndrome individuals may further present with hypotonia, prolonged QT and/or 2:1 atrioventricular conduction block, before the development of other non-cardiac symptoms.[2]

2. CACNA1C-Related Disorder (CRD), used for individuals with syndromic features affecting two or more organ systems who do not meet the Timothy syndrome dyad of prolonged QT plus a neurodevelopmental disorder.[2] Under this definition, an individual with CRD may still have a prolonged QT interval provided the specific TS dyad is not met.

3. Single organ system presentation, such as Long QT Type 8, in individuals whose genetic variant produces disease confined to a single organ system.[4][5][6][7] These isolated presentations fall within the broader CACNA1C-Related Disorders umbrella but are not classified as CRD.

Signs and symptoms

For Timothy syndrome and CRD, symptoms typically develop gradually but frequently begin from in utero.[4] All individuals with CACNA1C variants should be further assessed across all potentially affected organ systems, with ongoing follow-up on an annual basis to monitor for further symptoms driven by developmental changes.[2] The symptomatic traits associated with CACNA1C-Related Disorders are autosomal dominant.[3][8] CACNA1C-Related Disorders present with substantial phenotypic variability, but recurring features have been documented across the following systems:

Cardiac

Individuals may present with isolated cardiac features, with the most consistently reported cardiac feature being a prolonged QT interval. Individual QT durations vary widely, and cardiac risk does not correlate clearly with the degree of QT prolongation alone.[2] Structural findings include hypertrophic or non-compaction cardiomyopathy, congenital heart disease, and sinus node dysfunction.[2] Bradycardia, shortened atrioventricular conduction block (typically 2:1), and congenital structural cardiac malformations have also been reported in individuals with CRDs[2]. Shortened QT intervals have occasionally been reported in individuals with CACNA1C variants, but this is currently disputed.[9][2][10][11] CACNA1C variants are not associated with Brugada syndrome.[2]

There is likely an under-reporting of non-cardiac symptoms in patients seen for Long QT Type 8, therefore monitoring is required for the development of further symptoms.[2]

Neurodevelopmental and neurological

Intellectual disability, developmental delay, autism and Attention-Deficit Hyperactivity Disorder (ADHD) have all been reported in patients with CACNA1C-related disorders.[12][13] Hypotonia and epilepsy/seizures have also been reported in individuals with CACNA1C-related disorders.[12][13][4][14][15]

Endocrine

Hypoglycaemia is a recognised feature of CRDs.[4][16] Individuals with CRDs are at risk of hypoglycaemia during periods of physiological stress, such as viral infections.[17] Recent work shows hypoglycaemia in TS/CRD is driven by dysregulated glucose homeostasis, absent hyperinsulinism, and defects in glucagon secretion [18][2] and is considered clinically significant because it can compound arrhythmia risk.[2] Hypothermia has also been reported in CRDs.[4][2]

Gastrointestinal

Esophageal dysfunction or dysphagia, and/or constipation[4][19][1] have been reported in patients with CACNA1C variants. More specifically, some individuals with CACNA1C variants were reported to have gastric reflux, frequent vomiting, a severe gag reflex and/or difficulty swallowing.[4] In this study, one individual with CRD, in early life, had feeding intolerance and vomiting, alongside segmental ileal dilation.[19] Constipation is seen in >80% of individuals with Timothy syndrome.[4]

Dysmorphology and skeletal features

Syndactyly of the fingers and toes are frequent in patients with Timothy syndrome type 1,[14][20] whilst hip dysplasia is characteristic of Timothy syndrome Type 2.[12][16][4] Facial dysmorphology (round face, broad forehead or receding hairline, thin upper lip)[1] and dental abnormalities (small or misplaced teeth, severe caries and cavities) have also been identified in some patients with CRDs.[1]

Guidance for the reporting of CACNA1C variants

As stated by the 2026 consensus,[2] diagnoses should follow the format: the CACNA1C-related disorder nomenclature included as a top-level term, followed by a phenotypic description and the exact protein and genomic change, e.g.; term first, then phenotypic description, then exact variant, for example:

  • CACNA1C-related disorder
  • Developmental delay and hypotonia phenotype
  • p.Leu601Arg (HG38 g.2567701 T>G)

Genetics

CACNA1C is a large gene, with 47 coding exons and more than 240 transcripts showing developmental-stage and tissue-specific splicing.[21][22] Two of these exons, 8 and 8A, are spliced in a mutually exclusive manner and correlate with distinct clinical presentations, such as seen in Timothy syndrome type 1 and type 2.[2]

The majority of rare pathogenic CACNA1C variants in individuals arise de novo (not inherited from the maternal or paternal germline)[2]. In a smaller proportion of cases, the variant is inherited - passed down from an affected parent to their child in an autosomal dominant manner, rather than arising de novo. In a few cases CRDs can be caused by germline mosaicism.[23][24] Mosaicism can occur in two different ways in CRDs. A parent may carry the variant in only some of their cells (postzygotically), and so be unaffected or only mildly affected, yet still pass a full copy of the variant to a child, who then has it in every cell.[25] Alternatively, the affected individual may themselves be mosaic, with the variant present in only some of their own cells - which can produce a milder or more variable phenotype depending on which tissues are affected.[26] Genetic testing of parents and the affected child can be used to test if a variant is de novo or from mosaicism.[27] To test for mosaicism, deep sequencing, such as Haloplex, can be used.[28]

Timothy syndrome is caused by missense variants in CACNA1C, predominantly p.G406R and p.G402S.[1] Individuals with Type 1 predominantly carry p.G406R in exon 8A, whilst individuals with Type 2 predominantly harbour p.G406R in exon 8.[4][3] Further variants (p.R324W,[12] p.V403M,[12] p.G402S,[3] p.E407G,[29] p.E407A,[30] p.C1021R,[24][19] p.I1166T,[31][32][30] and p.A1473G[33] have been identified in patients with a Type 2 diagnosis. Phenotypic variability has been noted in patients with the same CACNA1C variants.[12] Rodan et al. (2021) reported that individuals with the following CACNA1C variants also had epilepsy: p.F166L, p.K177R, p.R324W, p.M611T, p.L614R, p.L614P, p.L657F, p.V1187A, p.L1408V, and p.V1411L.[12][lower-alpha 2] CRDs are caused by a wide variety of genetic variants, some of which have been described in the supplementary documents of the 2026 consensus.[2]

Variants of uncertain significance in CACNA1C

There are a large number of individuals who carry a rare CACNA1C variant that is yet to be classified as likely pathogenic or pathogenic, these are referred to as variants of unknown or uncertain significance (VUS). Further evidence may be required for VUS, for example, in regard to a variant's functional impact on the CaV1.2 channel.[34] If VUS patients present with symptoms of CACNA1C-related disorder, it is reasonable to clinically screen for other organ involvement; to determine if there is further clinical evidence of a CACNA1C-related disorder.[2]

Mechanism

The variant, p.G406R in exon 8A, produces a gain-of-function effect on the CaV1.2 channel, with significant changes to channel activation, voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI).[1][3][35][36] A hyperpolarised (left) shift in the channel's activation curve is coupled with reduced VDI and CDI, resulting in increased calcium influx during the cardiac action potential.[16][35]

This gating profile is not shared by all CACNA1C variants: p.G402S instead produces a rightward shift in channel activation together with a reduction in CDI, an electrophysiological signature distinct from, and in some respects opposite to, that of p.G406R.[35][36] Effects also extend beyond channel gating. In a mouse model, the p.G406R variant has been shown to reduce synaptic inhibition and alter long-term potentiation at hippocampal synapses, with additional effects reported on cortical differentiation and interneuron migration, suggesting mechanisms for the neurodevelopmental and neurological features of the disorder that are distinct from its cardiac effects.[37]

This divergence between p.G406R and p.G402S illustrates a broader pattern. Although pathogenic missense variants are often described as producing a straightforward "gain-of-function", the consensus statement is explicit that this framework does not fully account for the clinical variability observed across individuals and variants. Different pathogenic variants can alter Cav 1.2 function through varied mechanisms, including changes to cell-surface channel expression via altered degradation, and increased basal gene transcription through excitation–transcription coupling.[31][38][35][39][40] Because of this mechanistic heterogeneity, clinical pathogenicity should not be inferred from a variant's classification as simple "gain-of-function" or "loss-of-function" alone.[2] Many CACNA1C variants are yet to be tested functionally to decipher the mechanism of their specific gating effects.

Novel variants should be tested functionally in established model systems.[2] Further, as stated by Walsh et al, 2024,[41] reanalysis and re-evaluation of previously reported variants of uncertain significance (VUS) should be a priority as new evidence via literature and in-silico tools are published. Patch clamp analysis can be used to measure the effect of variants on CaV1.2 current density and voltage-dependent activation.[12]

Tissue-specific expression

CaV1.2 is widely expressed across almost all tissues;[1] and altered activation of the CaV1.2 channel is considered the underlying pathological mechanisms behind CACNA1C-related disorders.[42] This broad expression is complicated by extensive tissue-specific alternative splicing: CACNA1C's more than 240 transcripts are differentially expressed by tissue type, altering CaV1.2 channel function in a tissue-dependent manner.[4][22][21] This tissue-specific splicing is considered a contributing factor to the organ-specific development of symptoms in CRDs.[22]

Phenotypic variability

Variability between individuals carrying the same CACNA1C variant has been attributed to several factors. Germline mosaicism can contribute to irregular penetrance and phenotypic variability across CACNA1C-related disorders.[28] Tissue-specific splicing may also play a role: approximately 80% of CaV1.2 mRNA expressed in the heart and brain contains exon 8, with the remaining 20% expressing exon 8A.[1][43] Whether the expression ratio explains the phenotypic split has not been established. Developmental changes in CACNA1C expression have also been proposed to explain the delayed onset of non-cardiac symptoms in some individuals, with splice variation, mosaicism or reduced penetrance suggested as possible reasons why some carriers present with disease confined to a single organ.[4]

Guidelines for clinical care

Individuals with a likely pathogenic or pathogenic CACNA1C variant require a multidisciplinary clinical health check, with a minimum review of their cardiac, neurodevelopmental, musculoskeletal and endocrine systems.[2]

Patients with CACNA1C-related disorder require symptoms to be treated as they occur, with individuals requiring personalised interventions based on specific disease presentation, as stated in the 2026 consensus.[2]

The long-term evolution of outcomes and symptoms, especially in those without prolonged QT, are not currently known. However, several individuals are now well into mid-life.[4][13]

The 2026 consensus guidelines[2] for minimum standard of care include:

Timothy syndrome CACNA1C-related disorder and Long QT Type 8
Recommendation Recommendation
Annual cardiac review including electrocardiography (ECG/EKG) Annual cardiac review including electrocardiography (ECG/EKG)
Consider early insertion of implantable cardioverter-defibrillators (ICDs) Case-specific use of ICDs and loop recorders in those with borderline or prolonged QT interval (age and sex adjusted)
Annual neurodevelopmental reviews whilst <18 years of age Annual neurodevelopmental reviews whilst <18 years of age where evidence of developmental delay, neurodevelopmental or neurological features
Periodic home ambulatory EEG to identify potential seizure activity, with review by neurologist Neurological assessment including EEG where evidence of developmental delay, neurodevelopmental or neurological features
Home glucose monitoring, hypoglycaemia and seizure rescue kits with appropriate training Family/ general practitioner annual review to include endocrine, neurological and cardiac health status
Annual endocrine and neurology review

Cardiac

Implantable cardioverter-defibrillators (ICDs) have been highlighted as the current most effective treatment for CRDs.[2][44][6][45] Implantation of ICDs in early life have also been shown to decrease mortality risk.[4][16][36] Surgical interventions such as left cardiac sympathetic denervation, which attenuates heterogeneous sympathetic myocardial innervation, have also demonstrated effectiveness.[4][16][36][46] Beta blocker medication may not prevent arrhythmias or sudden cardiac death, so they are not recommended as a standalone treatment.[2] Calcium-channel blockers are not effective in Timothy syndrome due to the complex gating changes in Ca v1.2.[2]

Epilepsy

Epilepsy is frequently seen across CACNA1C-related disorders, with some seizures being ineffective against standard treatments.[12][17][13][47] Individuals with CACNA1C-related disorders, who present with seizures, should have neurological evaluations and seizure rescue medications available in all environments (for example: home, work or school).[2]

Hypoglycaemia

Hypoglycaemia has been noted in patients with CACNA1C-related disorders,[1][3][4] particularly during states of physiological stress including viral illnesses.[2] Hypoglycaemia, together with arrhythmias and lower seizure thresholds can be dangerous. Individuals with CRDs should monitor blood glucose levels routinely and have rescue kits on hand (e.g. glucose tablets or gel, fruit juice or sugary drinks/candy when blood sugar is low).[2]

Neurodevelopmental

Most individuals with CACNA1C-related disorders will have some form of developmental delay, particularly speech related.[4][15][13] Autism is prevalent across CACNA1C-related disorders, with ADHD, neurosensory and neuromuscular features also being noted in individuals.[4][12][13][2] Individuals with CACNA1C-related disorders should have personalised support plans for education and work environments.[2]

Further symptoms for monitoring

Children with CACNA1C-related disorders have frequent infections (due to an altered immune function), abnormal dental problems (frequent cavities and small, displaced teeth),[1][4][15] gastroesophageal reflux, vomiting and congenital gastrointestinal defects[4][19] and chronic constipation.[1][4]

Prognosis

Long-term outcome data remain limited for CRDs. Affected individuals may develop new syndromic features over their lifespan as CaV1.2 expression changes with age, and the consensus statement therefore recommends consistent, ongoing multidisciplinary follow-up rather than a single diagnostic assessment.[2] Prognosis varies considerably across CRDs and is closely tied to phenotype and, historically, to the timing of diagnosis and cardiac intervention. Improved survival in more recent cohorts may be caused by earlier diagnosis and implantation of cardioverter-defibrillators, with long-term outcomes continuing to improve with consistent multidisciplinary follow-up.[2] For information on prognosis in Timothy syndrome, see Timothy syndrome § Prognosis.

Epidemiology

CACNA1C-related disorders are ultra-rare, with current estimates placing prevalence at <1 in 1,000,000 individuals[2]. Within CACNA1C-Related Disorders, Timothy syndrome is the most extensively studied and was first characterised by the Keating and Splawski group in 2004.[1]

History

Under the umbrella of CACNA1C-related disorders, Timothy syndrome was the first to be identified. Timothy syndrome's clinical features were described before its genetic cause was known. A 1992 German case report identified a male infant with a prolonged QT interval and syndactyly, whose father also had carpal fusion, raising suspicion of an autosomal dominant condition with no genetic cause yet established.[48] A 1995 US case series identified three children with prolonged QT arrhythmia and syndactyly, again without a known genetic association.[49]

The condition was formally characterised in 2004 by the Keating and Splawski labs, who identified the p.G406R missense variant in exon 8A of CACNA1C in 13 children, arising de novo in 12 of 13 families (the remaining family showed maternal mosaicism). The original description characterised it as a prolonged QT arrhythmia disorder (Long QT Type 8) with multisystem involvement, including congenital heart disease, syndactyly, immune deficiency and autism.[1] In 2005, the same labs reported two further individuals with Timothy syndrome but without syndactyly - one with a de novo p.G406R variant in exon 8, presenting with hip dysplasia, and one with a de novo p.G402S variant, also in exon 8, establishing what would later be recognised as Timothy syndrome type 2.[3]

Between 2013 and 2018, several studies screened CACNA1C in cohorts with isolated, non-syndromic Long QT syndrome, absent of the broader features of Timothy syndrome. Boczek et al, (2013)[31] identified p.P857R in a family with symptoms spanning Long QT syndrome, without non-cardiac symptoms. They showed experimentally that p.P857R has a gain of function effect on channel function. Screening a further 102 non-syndromic Long QT patients, Boczek identified p.K834E, p.P857L, and p.R1906Q in 3 unrelated individuals, although channel function was not tested experimentally.[31] A 2014 screen of 278 individuals with prolonged QT and no non-cardiac features identified five further variants (p.P381S, M456I, A582D, R858H and G1783C), with available family segregation data showing prolonged QT and cardiac abnormalities co-segregating with the variant.[38] Wemhöner et al, (2015) screened 540 unrelated Long QT patients, again without Timothy syndrome features, identifying six variants (p.A28T, p.R860G, p.I1166T, p.I1166V, p.I1475M and p.E1496K) shown to functionally prolong the action potential through a gain-of-function mechanism.[32] Gardner et al, (2018) reported p.R858H segregating with isolated prolonged QT across 26 individuals in a five-generation family.[50] Most of these early studies did not include long-term follow-up evaluation, complicating the assessment of a cardiac-specific phenotype. Walsh et al, (2018) identified three individuals with p.G406R in exon 8A, all of whom had syndactyly and structural cardiac defects, and two individuals with mosaic p.G406R in exon 8, neither of whom had syndactyly but one of whom had hip dysplasia and global developmental delay - a pattern consistent with hip dysplasia being a Type 2, not Type 1, feature.[16] Rodan et al, (2021) studied 25 individuals with CACNA1C variants, including 13 unrelated individuals with de novo non-truncating variants (p.F166L, p.K177R, p.R324W, p.V403M, p.L601R, p.M611T, p.L614R, p.L614P, p.L657F, p.I743del, p.V1187A, p.L1408V or p.V1411L), and found defects spanning cardiac, neurodevelopmental, neurological, orthopaedic and dysmorphic features in most.[12] Borbás et al, (2022) reviewed the 2004-2019 literature and identified 56 Timothy syndrome index cases alongside 6 CRD cases and 20 isolated Long QT Type 8 cases.[14] Levy et al, (2022) surveyed 24 individuals with CACNA1C-Related Disorders and found developmental delay the most commonly reported neuropsychiatric feature (92%), followed by incoordination, hypotonia, autism spectrum disorder and, less commonly, seizures and ADHD, with no significant difference in symptom rates between those with and without arrhythmia.[13]

By 2024, several studies pointed toward a more consistently multisystem picture. Matthews et al, (2024) studied 44 individuals with Timothy syndrome and found high rates of premature birth (43% before 37 weeks), often prompted by fetal bradycardia from atrioventricular block, with syndactyly present in 91% of cases.[20] A separate 2024 systematic review by Cipriano et al, examined 36 individuals with neurologically-predominant CACNA1C-related presentations lacking cardiac conduction defects, finding intellectual disability, hypotonia, ataxia, seizures and autism as the most frequent features.[15] The same year, the first natural history study for Timothy Syndrome surveyed the parents of 87 individuals with rare CACNA1C variants.[4] The study found that Long QT syndrome, neurodevelopmental impairment, hypoglycaemia, and respiratory issues occurred at comparable rates across all groups of genotype and initial diagnosis, including those previously classified as having "non-syndromic" cardiac-only Timothy syndrome (Long QT Type 8). As the first natural history study of the condition, it concluded that Timothy syndrome and CRD are consistently multisystemic, and that hypoglycaemia and respiratory dysfunction represent significant, previously under recognised life threatening risks alongside cardiac arrhythmia. A 2025 study, Brogger et al, identified a further 18 individuals with likely pathogenic or pathogenic CACNA1C variants across six variants (p.G402S in exon 8A and p.G406R, p.R518C, p.R518H, p.R858H, p.R860Q in exon 8).[51] It is noted that Brogger et al, placed p.G402S in exon 8A, differing from the exon assignment given in Splawski's original description and the 2026 consensus statement.[51][1][2]

This growing but fragmented literature culminated in 2026, when Underwood et al, in partnership with an international panel of CACNA1C experts and the Timothy Syndrome Alliance patient community, published the first international consensus statement on diagnostic language and clinical management through a Delphi process.[2] Underwood et al, formally coining the term "CACNA1C-Related Disorders" and estimating population prevalence at <1 in 1,000,000.[2] The TSA is credited as a collaborative author group on the paper.[2] A separate 2026 study by Hall et al. found that CACNA1C produces largely distinct CaV1.2 isoforms in brain, heart and aortic tissue, raising the prospect of tissue-selective therapeutics that could target the neuropsychiatric-relevant brain isoforms without affecting the cardiac isoforms responsible for arrhythmia risk.[22]

Patient advocacy group

The Timothy Syndrome Alliance (TSA) is a patient advocacy organisation supporting individuals and families affected by CACNA1C-related disorders, including Timothy syndrome and Long QT Type 8.[2] As of October 2025, TSA's global CACNA1C Community Registry includes 104 individuals.[2] CredibleMeds maintains a list of QT-prolonging medications relevant to individuals with CRDs.

Notes

  1. ↑ Online Mendelian Inheritance in Man (OMIM) 620029 is currently labelled as "Neurodevelopmental Disorder with Hypotonia, Language Delay, and Skeletal Defects with or without Seizures". This will be updated to CACNA1C-Related Disorder in due course.
  2. ↑ NCBI CACNA1C RefSeq Accession: NM_000719.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Splawski, Igor; Timothy, Katherine W.; Sharpe, Leah M.; Decher, Niels; Kumar, Pradeep; Bloise, Raffaella; Napolitano, Carlo; Schwartz, Peter J. et al. (October 2004). "CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism" (in en). Cell 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078. https://linkinghub.elsevier.com/retrieve/pii/S0092867404008426. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 Underwood, Jack F. G.; Timothy, Katherine W.; Tyroll, Holly; Levy, Rebecca J.; Dick, Ivy E.; Pitt, Geoffrey S.; Tunbridge, Elizabeth M.; Baban, Anwar et al. (2026-07-09). "Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement" (in en). European Journal of Human Genetics. doi:10.1038/s41431-026-02178-8. ISSN 1018-4813. PMID 42426153. https://www.nature.com/articles/s41431-026-02178-8. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Splawski, Igor; Timothy, Katherine W.; Decher, Niels; Kumar, Pradeep; Sachse, Frank B.; Beggs, Alan H.; Sanguinetti, Michael C.; Keating, Mark T. (2005-06-07). "Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations". Proceedings of the National Academy of Sciences 102 (23): 8089–8096. doi:10.1073/pnas.0502506102. PMID 15863612. Bibcode: 2005PNAS..102.8089S. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 Timothy, Katherine W.; Bauer, Rosemary; Larkin, Kerry A.; Walsh, Edward P.; Abrams, Dominic J.; Gonzalez Corcia, Cecilia; Valsamakis, Alexandra; Pitt, Geoffrey S. et al. (2024-11-23). "A Natural History Study of Timothy Syndrome" (in en). Orphanet Journal of Rare Diseases 19 (1). doi:10.1186/s13023-024-03445-x. ISSN 1750-1172. PMID 39580446. 
  5. ↑ Bauer, Rosemary; Timothy, Katherine W.; Golden, Andy (2021-05-17). "Update on the Molecular Genetics of Timothy Syndrome". Frontiers in Pediatrics 9. doi:10.3389/fped.2021.668546. ISSN 2296-2360. PMID 34079780. 
  6. ↑ 6.0 6.1 Yu, Liwei; Neves, Raquel; Bos, Martijn M.; Tester, David J.; Sardana, Mayank; Giudicessi, John R.; Ackerman, Michael J. (August 2025). "Evaluation of CACNA1C-Positive Patients Evaluated in a Tertiary Genetic Heart Rhythm Clinic" (in en). Journal of Cardiovascular Translational Research 18 (4): 888–899. doi:10.1007/s12265-025-10638-7. ISSN 1937-5387. PMID 40526200. https://link.springer.com/10.1007/s12265-025-10638-7. 
  7. ↑ Landstrom, Andrew P.; Boczek, Nicole J.; Ye, Dan; Miyake, Christina Y.; De la Uz, Caridad M.; Allen, Hugh D.; Ackerman, Michael J.; Kim, Jeffrey J. (October 2016). "Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current" (in en). International Journal of Cardiology 220: 290–298. doi:10.1016/j.ijcard.2016.06.081. PMID 27390944. 
  8. ↑ Napolitano, Carlo; Priori, Silvia G. (1993), Adam, Margaret P.; Bick, Sarah; Mirzaa, Ghayda M. et al., eds., "CACNA1C-Related Disorders", GeneReviews® (Seattle (WA): University of Washington, Seattle), PMID 20301577, http://www.ncbi.nlm.nih.gov/books/NBK1403/, retrieved 2026-09-23 
  9. ↑ Hosseini, S. Mohsen; Kim, Raymond; Udupa, Sharmila; Costain, Gregory; Jobling, Rebekah; Liston, Eriskay; Jamal, Seema M.; Szybowska, Marta et al. (2018-09-18). "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome" (in en). Circulation 138 (12): 1195–1205. doi:10.1161/CIRCULATIONAHA.118.035070. ISSN 0009-7322. PMID 29959160. 
  10. ↑ Antzelevitch, Charles; Pollevick, Guido D.; Cordeiro, Jonathan M.; Casis, Oscar; Sanguinetti, Michael C.; Aizawa, Yoshiyasu; Guerchicoff, Alejandra; Pfeiffer, Ryan et al. (2007-01-30). "Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death" (in en). Circulation 115 (4): 442–449. doi:10.1161/CIRCULATIONAHA.106.668392. ISSN 0009-7322. PMID 17224476. 
  11. ↑ Walsh, Roddy; Adler, Arnon; Amin, Ahmad S; Abiusi, Emanuela; Care, Melanie; Bikker, Hennie; Amenta, Simona; Feilotter, Harriet et al. (2022-04-14). "Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death" (in en). European Heart Journal 43 (15): 1500–1510. doi:10.1093/eurheartj/ehab687. ISSN 0195-668X. PMID 34557911. PMC 9009401. https://academic.oup.com/eurheartj/article/43/15/1500/6374783. 
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 Rodan, Lance H.; Spillmann, Rebecca C.; Kurata, Harley T.; Lamothe, Shawn M.; Maghera, Jasmine; Jamra, Rami Abou; Alkelai, Anna; Antonarakis, Stylianos E. et al. (October 2021). "Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations" (in en). Genetics in Medicine 23 (10): 1922–1932. doi:10.1038/s41436-021-01232-8. PMID 34163037. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Levy, Rebecca J.; Timothy, Katherine W.; Underwood, Jack F.G.; Hall, Jeremy; Bernstein, Jonathan A.; Pașca, Sergiu P. (January 2023). "A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder" (in en). Pediatric Neurology 138: 101–106. doi:10.1016/j.pediatrneurol.2022.10.013. PMID 36436328. https://linkinghub.elsevier.com/retrieve/pii/S0887899422002296. 
  14. ↑ 14.0 14.1 14.2 Borbás, János; Vámos, Máté; Hategan, Lidia; Hanák, Lilla; Farkas, Nelli; Szakács, Zsolt; Csupor, Dezső; Tél, Bálint et al. (2022-11-29). "Geno- and phenotypic characteristics and clinical outcomes of CACNA1C gene mutation associated Timothy syndrome, "cardiac only" Timothy syndrome and isolated long QT syndrome 8: A systematic review". Frontiers in Cardiovascular Medicine 9. doi:10.3389/fcvm.2022.1021009. ISSN 2297-055X. PMID 36523353. 
  15. ↑ 15.0 15.1 15.2 15.3 Cipriano, Lorenzo; Piscopo, Raffaele; Aiello, Chiara; Novelli, Antonio; Iolascon, Achille; Piscopo, Carmelo (2024-04-30). "Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation" (in en). Children 11 (5): 541. doi:10.3390/children11050541. ISSN 2227-9067. PMID 38790536. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Walsh, Mark A; Turner, Christian; Timothy, Katherine W; Seller, Neil; Hares, Dominic L; James, Andrew F; Hancox, Jules C; Uzun, Orhan et al. (2018-02-01). "A multicentre study of patients with Timothy syndrome" (in en). EP Europace 20 (2): 377–385. doi:10.1093/europace/euw433. ISSN 1099-5129. PMID 28371864. https://academic.oup.com/europace/article/20/2/377/3089666. 
  17. ↑ 17.0 17.1 Bozarth, Xiuhua; Dines, Jennifer N.; Cong, Qian; Mirzaa, Ghayda M.; Foss, Kimberly; Lawrence Merritt, J.; Thies, Jenny; Mefford, Heather C. et al. (December 2018). "Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late-onset epilepsy" (in en). American Journal of Medical Genetics Part A 176 (12): 2733–2739. doi:10.1002/ajmg.a.40657. ISSN 1552-4825. PMID 30513141. 
  18. ↑ Matsui, Maiko; Lynch, Lauren E.; Distefano, Isabella; Galante, Allison; Gade, Aravind R.; Wang, Hong-Gang; Gómez-Banoy, Nicolas; Towers, Patrick et al. (2024-10-17). "Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome". Nature Communications 15 (1): 8980. doi:10.1038/s41467-024-52885-3. ISSN 2041-1723. PMID 39420001. Bibcode: 2024NatCo..15.8980M. 
  19. ↑ 19.0 19.1 19.2 19.3 Nugud, Ahmed A.; ELkholy, Nermeen Mahmoud; Omar, Awad Alkarim; Qazi, Abid; Tzivinikos, Christos; Chencheri, Nidheesh; Khan, Sabina; Ba'Ath, Muhammad Eyad (2021-04-27). "Case Report: Expanding the Phenotypic Spectrum of Timothy Syndrome Type 1: A Sporadic Case With a de novo CACNA1C Pathogenic Variant and Segmental Ileal Dilatation". Frontiers in Pediatrics 9. doi:10.3389/fped.2021.634655. ISSN 2296-2360. PMID 33987151. 
  20. ↑ 20.0 20.1 Matthews, Alexandra; Timothy, Katherine; Golden, Andy; Gonzalez Corcia, M. Cecilia (2024). "International Cohort of Neonatal Timothy Syndrome" (in en). Neonatology 121 (3): 388–395. doi:10.1159/000535221. ISSN 1661-7800. PMID 38211567. https://karger.com/article/doi/10.1159/000535221. 
  21. ↑ 21.0 21.1 Clark, Michael B.; Wrzesinski, Tomasz; Garcia, Aintzane B.; Hall, Nicola A. L.; Kleinman, Joel E.; Hyde, Thomas; Weinberger, Daniel R.; Harrison, Paul J. et al. (January 2020). "Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain". Molecular Psychiatry 25 (1): 37–47. doi:10.1038/s41380-019-0583-1. ISSN 1476-5578. PMID 31695164. 
  22. ↑ 22.0 22.1 22.2 22.3 Hall, Nicola AL; Mould, Arne W.; Nassiri, Isar; Kudasheva, Sofia; Wright, David J.; Chen, Li; Arshad, Osama A.; Tao, Ran et al. (2026-09-11). "The psychiatric risk gene CACNA1C encodes distinct full-length isoforms in human brain, heart and aorta" (in en). Molecular Psychiatry (Nature Publishing Group): 1–10. doi:10.1038/s41380-026-03890-z. ISSN 1476-5578. PMID 42728318. https://www.nature.com/articles/s41380-026-03890-z. 
  23. ↑ Fröhler, Sebastian; Kieslich, Moritz; Langnick, Claudia; Feldkamp, Mirjam; Opgen-Rhein, Bernd; Berger, Felix; Will, Joachim C; Chen, Wei (December 2014). "Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)" (in en). BMC Medical Genetics 15 (1). doi:10.1186/1471-2350-15-48. ISSN 1471-2350. PMID 24773605. 
  24. ↑ 24.0 24.1 Dufendach, Keith A.; Timothy, Katherine; Ackerman, Michael J.; Blevins, Benjamin; Pflaumer, Andreas; Etheridge, Susan; Perry, James; Blom, Nico A. et al. (April 2018). "Clinical Outcomes and Modes of Death in Timothy Syndrome" (in en). JACC: Clinical Electrophysiology 4 (4): 459–466. doi:10.1016/j.jacep.2017.08.007. PMID 30067485. https://linkinghub.elsevier.com/retrieve/pii/S2405500X17306904. 
  25. ↑ Thorpe, Jeremy; Osei-Owusu, Ikeoluwa A.; Avigdor, Bracha Erlanger; Tupler, Rossella; Pevsner, Jonathan (2020-11-23). "Mosaicism in Human Health and Disease". Annual Review of Genetics 54 (1): 487–510. doi:10.1146/annurev-genet-041720-093403. ISSN 0066-4197. PMID 32916079. 
  26. ↑ Dufendach, Keith A.; Giudicessi, John R.; Boczek, Nicole J.; Ackerman, Michael J. (2013-06-01). "Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome". Pediatrics 131 (6): e1991–e1995. doi:10.1542/peds.2012-2941. ISSN 0031-4005. PMID 23690510. PMC 3666110. https://doi.org/10.1542/peds.2012-2941. 
  27. ↑ Mohiuddin, Mohiuddin; Kooy, R. Frank; Pearson, Christopher E. (2022-09-26). "De novo mutations, genetic mosaicism and human disease". Frontiers in Genetics 13. doi:10.3389/fgene.2022.983668. ISSN 1664-8021. PMID 36226191. 
  28. ↑ 28.0 28.1 Baurand, Amandine; Falcon-Eicher, Sylvie; Laurent, Gabriel; Villain, Elisabeth; Bonnet, Caroline; Thauvin-Robinet, Christel; Jacquot, Caroline; Eicher, Jean-Christophe et al. (February 2017). "Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing" (in en). American Journal of Medical Genetics Part A 173 (2): 531–536. doi:10.1002/ajmg.a.38045. ISSN 1552-4825. PMID 27868338. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38045. 
  29. ↑ Po', Chiara; Zordan, Roberta; Vecchi, Marilena; Cerutti, Alessia; Sartori, Stefano; Trevisson, Eva; Ludwig, Kathrin; Castaldi, Biagio et al. (November 2019). "Photosensitive epilepsy and long QT: expanding Timothy syndrome phenotype" (in en). Clinical Neurophysiology 130 (11): 2134–2136. doi:10.1016/j.clinph.2019.09.003. PMID 31563812. https://linkinghub.elsevier.com/retrieve/pii/S1388245719312222. 
  30. ↑ 30.0 30.1 Colson, Cindy; Mittre, Hervé; Busson, Adeline; Leenhardt, Antoine; Denjoy, Isabelle; Fressard, Véronique; Troadec, Yann (July 2019). "Unusual clinical description of adult with Timothy syndrome, carrier of a new heterozygote mutation of CACNA1C" (in en). European Journal of Medical Genetics 62 (7): 103648. doi:10.1016/j.ejmg.2019.04.005. PMID 30998997. https://linkinghub.elsevier.com/retrieve/pii/S1769721218308310. 
  31. ↑ 31.0 31.1 31.2 31.3 Boczek, Nicole J.; Best, Jabe M.; Tester, David J.; Giudicessi, John R.; Middha, Sumit; Evans, Jared M.; Kamp, Timothy J.; Ackerman, Michael J. (June 2013). "Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C , Linked to Autosomal Dominant Long QT Syndrome" (in en). Circulation: Cardiovascular Genetics 6 (3): 279–289. doi:10.1161/CIRCGENETICS.113.000138. ISSN 1942-325X. PMID 23677916. 
  32. ↑ 32.0 32.1 Wemhöner, Konstantin; Friedrich, Corinna; Stallmeyer, Birgit; Coffey, Alison J.; Grace, Andrew; Zumhagen, Sven; Seebohm, Guiscard; Ortiz-Bonnin, Beatriz et al. (March 2015). "Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome" (in en). Journal of Molecular and Cellular Cardiology 80: 186–195. doi:10.1016/j.yjmcc.2015.01.002. PMID 25633834. https://linkinghub.elsevier.com/retrieve/pii/S0022282815000036. 
  33. ↑ Gillis, Jane; Burashnikov, Elena; Antzelevitch, Charles; Blaser, Susan; Gross, Gil; Turner, Lesley; Babul-Hirji, Riyana; Chitayat, David (January 2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: Expanding the spectrum of Timothy syndrome" (in en). American Journal of Medical Genetics Part A 158A (1): 182–187. doi:10.1002/ajmg.a.34355. ISSN 1552-4825. PMID 22106044. 
  34. ↑ Tan, C.; Shen, Q.; Vandenberg, J.; Ng, C. (July 2024). "Establishing a Functional Genomics Assay to Assess Clinical Variants in CACNA1C-Related Disorders" (in en). Heart, Lung and Circulation 33: S117. doi:10.1016/j.hlc.2024.04.210. https://linkinghub.elsevier.com/retrieve/pii/S1443950624004104. 
  35. ↑ 35.0 35.1 35.2 35.3 Dick, Ivy E.; Joshi-Mukherjee, Rosy; Yang, Wanjun; Yue, David T. (2016-01-29). "Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation". Nature Communications 7 (1). doi:10.1038/ncomms10370. ISSN 2041-1723. PMID 26822303. 
  36. ↑ 36.0 36.1 36.2 36.3 Bamgboye, Moradeke A.; Traficante, Maria K.; Owoyemi, Josiah; DiSilvestre, Deborah; Vieira, Daiana C.O.; Dick, Ivy E. (December 2022). "Impaired CaV1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8" (in en). Journal of Molecular and Cellular Cardiology 173: 92–100. doi:10.1016/j.yjmcc.2022.10.003. PMID 36272554. 
  37. ↑ Sanderson, Jennifer L.; Freund, Ronald K.; Castano, Anna M.; Benke, Timothy A.; Dell'Acqua, Mark L. (December 2022). "The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome". Neuropharmacology 220. doi:10.1016/j.neuropharm.2022.109271. ISSN 0028-3908. PMID 36162529. PMC 9644825. https://doi.org/10.1016/j.neuropharm.2022.109271. 
  38. ↑ 38.0 38.1 Fukuyama, Megumi; Wang, Qi; Kato, Koichi; Ohno, Seiko; Ding, Wei-Guang; Toyoda, Futoshi; Itoh, Hideki; Kimura, Hiromi et al. (December 2014). "Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes" (in en). EP Europace 16 (12): 1828–1837. doi:10.1093/europace/euu063. ISSN 1532-2092. PMID 24728418. https://academic.oup.com/europace/article-lookup/doi/10.1093/europace/euu063. 
  39. ↑ Servili, Evrim; Trus, Michael; Sajman, Julia; Sherman, Eilon; Atlas, Daphne (August 2020). "Elevated basal transcription can underlie timothy channel association with autism related disorders" (in en). Progress in Neurobiology 191. doi:10.1016/j.pneurobio.2020.101820. PMID 32437834. https://linkinghub.elsevier.com/retrieve/pii/S0301008220300757. 
  40. ↑ Herold, Kevin G.; Bamgboye, Moradeke A.; Vieira, Daiana C.O.; Brown, Schuyler; DiSilvestre, Deborah; Owoyemi, Josiah O.; Gudmundsson, Emma; Dick, Ivy E. (February 2024). "Exploring the role of CaV1.2 dysfunction in the development of autism spectrum disorder using iPSC-derived neurons" (in en). Biophysical Journal 123 (3): 112a. doi:10.1016/j.bpj.2023.11.794. Bibcode: 2024BpJ...123..112H. https://linkinghub.elsevier.com/retrieve/pii/S0006349523014947. 
  41. ↑ Walsh, Nicola; Cooper, Aislinn; Dockery, Adrian; O'Byrne, James J (2024-01-31). "Variant reclassification and clinical implications" (in en). Journal of Medical Genetics 61 (3): 207–211. doi:10.1136/jmg-2023-109488. ISSN 0022-2593. PMID 38296635. https://jmg.bmj.com/content/61/3/207. 
  42. ↑ Ferron, Laurent; Zamponi, Gerald W. (2022-11-07). "The road to the brain in Timothy syndrome is paved with enhanced CaV1.2 activation gating" (in en). Journal of General Physiology 154 (11). doi:10.1085/jgp.202213272. ISSN 0022-1295. PMID 36264243. PMC 9587385. https://rupress.org/jgp/article/154/11/e202213272/213558/The-road-to-the-brain-in-Timothy-syndrome-is-paved. 
  43. ↑ Stockner, Thomas; Koschak, Alexandra (July 2013). "What can naturally occurring mutations tell us about Cav1.x channel function?" (in en). Biochimica et Biophysica Acta (BBA) - Biomembranes 1828 (7): 1598–1607. doi:10.1016/j.bbamem.2012.11.026. PMID 23219801. 
  44. ↑ Chen, Xiaoyu; Birey, Fikri; Li, Min-Yin; Revah, Omer; Levy, Rebecca; Thete, Mayuri Vijay; Reis, Noah; Kaganovsky, Konstantin et al. (2024-04-25). "Antisense oligonucleotide therapeutic approach for Timothy syndrome" (in en). Nature 628 (8009): 818–825. doi:10.1038/s41586-024-07310-6. ISSN 0028-0836. PMID 38658687. Bibcode: 2024Natur.628..818C. 
  45. ↑ Jiang, Congshan; Zhang, Yanmin (2023). "Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics" (in en). Expert Reviews in Molecular Medicine 25. doi:10.1017/erm.2023.11. ISSN 1462-3994. PMID 37132248. 
  46. ↑ Dusi, Veronica; Pugliese, Luigi; De Ferrari, Gaetano M.; Odero, Attilio; Crotti, Lia; Dagradi, Federica; Castelletti, Silvia; Vicentini, Alessandro et al. (March 2022). "Left Cardiac Sympathetic Denervation for Long QT Syndrome" (in en). JACC: Clinical Electrophysiology 8 (3): 281–294. doi:10.1016/j.jacep.2021.09.002. PMID 35331422. https://linkinghub.elsevier.com/retrieve/pii/S2405500X21007866. 
  47. ↑ Stringer, Robin N.; Tang, Xuechen; Jurkovicova-Tarabova, Bohumila; Murphy, Mary; Liedl, Klaus R.; Weiss, Norbert (2025-03-25). "Functional characterization of a novel de novo CACNA1C pathogenic variant in a patient with neurodevelopmental disorder" (in en). Molecular Brain 18 (1). doi:10.1186/s13041-025-01195-w. ISSN 1756-6606. PMID 40133997. 
  48. ↑ Reichenbach, H.; Meister, E. M.; Theile, H. (April 1992). "[The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet]". Kinderarztliche Praxis 60 (2): 54–56. ISSN 0023-1495. PMID 1318983. 
  49. ↑ Marks, Melinda L; Whisler, Sandra L; Clericuzio, Carol; Keating, Mark (January 1995). "A new form of long QT syndrome associated with syndactyly" (in en). Journal of the American College of Cardiology 25 (1): 59–64. doi:10.1016/0735-1097(94)00318-K. PMID 7798527. https://linkinghub.elsevier.com/retrieve/pii/073510979400318K. 
  50. ↑ Gardner, R. J. McKinlay; Crozier, Ian G.; Binfield, Alex L.; Love, Donald R.; Lehnert, Klaus; Gibson, Kate; Lintott, Caroline J.; Snell, Russell G. et al. (January 2019). "Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy" (in en). Molecular Genetics & Genomic Medicine 7 (1). doi:10.1002/mgg3.476. ISSN 2324-9269. PMID 30345660. 
  51. ↑ 51.0 51.1 Brogger, M N; Cazon Varela, L; De La Higuera Romero, L; Fernandez Fernandez, X; Amor-Salamanca, A; Cardenas Reyes, I; Garcia Hernandez, S; Valverde Gomez, M et al. (2025-11-01). "Associated phenotypes of pathogenic CACNA1C variants in a large cohort of patients undergoing genetic testing". European Heart Journal 46 (Supplement_1). doi:10.1093/eurheartj/ehaf784.2648. ISSN 0195-668X. https://doi.org/10.1093/eurheartj/ehaf784.2648. 



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