CACNA1C-Related Disorders (CRDs) are a group of rare genetic conditions caused by genetic variants in the gene CACNA1C. CACNA1C encodes the voltage-gated calcium channel (CaV1.2), widely expressed throughout the body, subsequently causing a wide range of multi-system symptoms. The term CACNA1C-Related Disorders is an umbrella term that includes Timothy syndrome (), CACNA1C-Related Disorder () and single organ system presentations, such as Long QT Type 8 () (Figure 1). Individuals with CRDs typically present with multisystem involvement spanning neurological, neurodevelopmental, cardiac, endocrine, gastrointestinal, skeletal and immune dysregulation abnormalities (Figure 1). Severity of CRDs ranges from isolated cardiac arrhythmia to profound multisystem involvement, which can vary between individuals.
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:
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. 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. 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. Individuals with Type 2 predominantly harbour p.G406R in exon 8, presenting with a similar phenotype to Type 1 but with hip dysplasia.
Individuals with pathogenic CACNA1C variants in utero, presenting with bradycardia, should be suspected as Timothy syndrome individuals who require monitoring and follow-up assessment. 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. 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. 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. 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. 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. The symptomatic traits associated with CACNA1C-Related Disorders are autosomal dominant. 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. Structural findings include hypertrophic or non-compaction cardiomyopathy, congenital heart disease, and sinus node dysfunction. Bradycardia, shortened atrioventricular conduction block (typically 2:1), and congenital structural cardiac malformations have also been reported in individuals with CRDs. Shortened QT intervals have occasionally been reported in individuals with CACNA1C variants, but this is currently disputed. CACNA1C variants are not associated with Brugada syndrome.
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.
Neurodevelopmental and neurological Intellectual disability, developmental delay, autism and Attention-Deficit Hyperactivity Disorder (ADHD) have all been reported in patients with CACNA1C-Related Disorders. Hypotonia and epilepsy/seizures have also been reported in individuals with CACNA1C-Related Disorders.
Endocrine Hypoglycaemia is a recognised feature of CRDs. Individuals with CRDs are at risk of hypoglycaemia during periods of physiological stress, such as viral infections. Recent work shows hypoglycaemia in TS/CRD is driven by dysregulated glucose homeostasis, absent hyperinsulinism, and defects in glucagon secretion and is considered clinically significant because it can compound arrhythmia risk. Hypothermia has also been reported in CRDs.
Gastrointestinal Esophageal dysfunction or dysphagia, and/or constipation 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. In this study, one individual with CRD, in early life, had feeding intolerance and vomiting, alongside segmental ileal dilation. Constipation is seen in >80% of individuals with Timothy syndrome.
Dysmorphology and skeletal features Syndactyly of the fingers and toes are frequent in patients with Timothy syndrome type 1, whilst hip dysplasia is characteristic of Timothy syndrome Type 2. Facial dysmorphology (round face, broad forehead or receding hairline, thin upper lip) and dental abnormalities (small or misplaced teeth, severe caries and cavities) have also been identified in some patients with CRDs.
Guidance for the reporting of CACNA1C variants As stated by the 2026 consensus, 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. 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.
The majority of rare pathogenic CACNA1C variants in individuals arise de novo (not inherited from the maternal or paternal germline). 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. 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. 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. Genetic testing of parents and the affected child can be used to test if a variant is de novo or from mosaicism. To test for mosaicism, deep sequencing, such as Haloplex, can be used.
Timothy syndrome is caused by missense variants in CACNA1C, predominantly p.G406R and p.G402S. Individuals with Type 1 predominantly carry p.G406R in exon 8A, whilst individuals with Type 2 predominantly harbour p.G406R in exon 8. Further variants (p.R324W, p.V403M, p.G402S, p.E407G, p.E407A, p.C1021R, p.I1166T, and p.A1473G have been identified in patients with a Type 2 diagnosis. Phenotypic variability has been noted in patients with the same CACNA1C variants. 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. CRDs are caused by a wide variety of genetic variants, some of which have been described in the supplementary documents of the 2026 consensus.
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. 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.
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). 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.
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. 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.
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. 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. 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. Further, as stated by Walsh et al, 2024, 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.
Tissue-specific expression