Timothy Syndrome

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Definitions

3

Clinical disease framing for Timothy syndrome

Timothy syndrome is the classical syndromic CACNA1C gain-of-function phenotype defined by prolonged QT interval with malignant arrhythmia plus characteristic extracardiac developmental features, especially syndactyly and neurodevelopmental abnormalities.

CASE_DEFINITION Classical MONDO disease framing for the syndromic CACNA1C channelopathy

Show evidence (2 references)

PMID:15454078 SUPPORT Human Clinical

"Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism."

Landmark clinical report defining the classical multisystem Timothy syndrome phenotype.

PMID:41333400 SUPPORT Other

"We formalise the language around syndromic presentations linked to CACNA1C variants, reassert and demarcate the classical Timothy Syndrome phenotype, and define a new syndrome, CACNA1C-Related Disorder."

Recent consensus supports retaining a classical Timothy syndrome disease framing while acknowledging a broader CACNA1C-related disorder spectrum.

Molecular definition for Timothy syndrome

Molecularly, this entry captures heterozygous activating CACNA1C variants that impair Cav1.2 voltage-dependent inactivation and create persistent inward calcium current.

DIAGNOSTIC_CRITERIA Molecular anchoring of classical CACNA1C-related Timothy syndrome

Show evidence (1 reference)

PMID:15454078 SUPPORT In Vitro

"Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation."

Defines the core gain-of-function mechanism of Timothy syndrome at the channel level.

Fever-associated arrhythmia/seizure case-finding query for latent CACNA1C carriers

Proposed EHR/OMOP case-finding query: identify individuals with a new ventricular arrhythmia / QT-prolongation event or a new seizure within a short window after a documented febrile episode, absent a prior such event, as candidate latent or mild CACNA1C-spectrum cases. The query operationalizes the emerging fever_exacerbated_cav1.2 hypothesis (fever activates CaV1.2 and can unmask arrhythmia/seizures even in overtly normal carriers); a positive yield is itself partial evidence for that hypothesis.

PHENOTYPE_ALGORITHM EHR/OMOP case-finding; HYPOTHESIS-GENERATING, NOT a validated diagnostic or consensus phenotype algorithm. Predicated on an unproven mechanism (fever_exacerbated_cav1.2) whose human validity is an open question.

Febrile-onset rhythm disturbance or seizure

Documented fever (temperature or febrile-illness diagnosis code) followed within a short window (e.g. days) by a NEW ventricular arrhythmia / long-QT event or a new seizure, with no prior arrhythmia/seizure history. Temporal window and code sets to be specified at implementation.

Inclusion criteria

Documented febrile episode Elevated body temperature or a febrile-illness diagnosis code (index exposure).
New post-fever arrhythmia or seizure First ventricular arrhythmia / QT-prolongation event or first seizure occurring shortly after the febrile episode.

Exclusion criteria

Pre-existing arrhythmia or epilepsy Prior history of the same event type, which would confound the fever-provoked interpretation.

Show evidence (1 reference)

PMID:42426269 SUPPORT Model Organism

"elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk"

Model-system basis for the query: temperature elicited arrhythmia and seizure-like behavior in phenotypically normal cacna1c heterozygotes, motivating a search for analogous latent human cases.

Notes: Hypothesis-based, unvalidated case-finding query — not a consensus or gold-standard-validated phenotype algorithm. Its epistemic status is carried structurally by derivation_basis (MECHANISTIC_HYPOTHESIS), the validation_status object (PROPOSED), and attaches_to the fever-trigger pathophysiology node, so the hypothesis basis is inferred from the pathograph (fever_exacerbated_cav1.2). See monarch-initiative/dismech#6245.

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Inheritance

1

Autosomal dominant HP:0000006

Timothy syndrome is mechanistically an autosomal dominant gain-of-function disorder, although most classical cases reported so far have arisen de novo.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:15454078 SUPPORT Human Clinical

"In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R."

Recurrent heterozygous de novo pathogenic variants support a dominant disease architecture with most observed cases being sporadic.

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Mechanistic Hypotheses

1

Fever/elevated body temperature lowers the threshold for CaV1.2-driven arrhythmia and seizures

fever_exacerbated_cav1.2 EMERGING

Evidence balance 2 support

Elevated body temperature activates the CaV1.2 L-type calcium channel and is hypothesized to augment the mutant persistent inward calcium current, so febrile episodes may acutely unmask ventricular arrhythmia and lower the seizure threshold — even in CACNA1C carriers who are overtly normal at baseline. This frames fever as a modifiable risk factor and, at a population level, as a candidate signal for scanning electronic health records for latent or mild CACNA1C-spectrum cases (e.g. a new rhythm disturbance or seizure temporally following a documented fever). The hypothesis is currently supported by a zebrafish cacna1c model; its validity in human patients is an open question (see the linked HUMAN_MODEL_MISMATCH discussion). Downstream causal edges that belong to this hypothesis opt in via hypothesis_groups: [fever_exacerbated_cav1.2].

Pathograph links

Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold -> Ventricular tachyarrhythmia (torsade de pointes) INDIRECT KNOWN INTERMEDIATES Fever-driven enhancement of mutant CaV1.2 current lowers the threshold for triggered ventricular tachyarrhythmia. Intermediates: augmented persistent inward calcium current; early afterdepolarizations

Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold -> Fever-associated increased seizure susceptibility Fever-driven enhancement of mutant CaV1.2 current, together with neuropeptide dysregulation, lowers the seizure threshold.

Fever-associated increased seizure susceptibility -> Seizures Lowered seizure threshold manifests clinically as seizures, an established feature of Timothy syndrome that may be precipitated by fever.

Show evidence (2 references)

PMID:42426269 SUPPORT Model Organism

"elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk"

In a zebrafish cacna1c Timothy-syndrome model, raising temperature elicited arrhythmia and seizure-like behavior even in phenotypically normal heterozygotes, directly motivating the fever-exacerbation hypothesis.

PMID:42426269 SUPPORT Other

"fever, known to activate CaV1.2 channels, may exacerbate TS, yet its impact is poorly understood"

States the biophysical premise (fever activates CaV1.2) and that its impact on Timothy syndrome is not yet characterized in patients.

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Discussions and Knowledge Gaps

1

Does fever/elevated body temperature acutely exacerbate arrhythmia and seizure susceptibility in human CACNA1C carriers — including overtly normal heterozygotes — as it does in the zebrafish cacna1c model, and can this fever-provoked signal be used to find latent or mild CACNA1C-spectrum cases in electronic health records?

HUMAN MODEL MISMATCH OPEN gap_ts_fever_exacerbation_human_validity

Attached to

pathophysiology#Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold pathophysiology#Fever-associated increased seizure susceptibility

The fever-exacerbation effect — arrhythmia and seizure-like behavior elicited by elevated temperature even in phenotypically normal heterozygotes — is demonstrated in a zebrafish cacna1c model, and the underlying premise (fever activates CaV1.2) is established biophysics. What is NOT established is whether the same fever-provoked decompensation occurs in human carriers and at what temperature/threshold. This is a genuine human-model-validity gap rather than an absence of evidence: model-system data exist, but their translation to human disease is the open question. Resolving it matters both clinically (fever management as a modifiable intervention) and for the hypothesis-based EHR case-finding query captured in this entry's definitions.

Proposed experiments

EHR scan for fever-associated arrhythmia/seizure and CACNA1C enrichment

EHR cohort case-finding and genotype-enrichment analysis

exp_ts_fever_ehr_case_finding

In a genotype-linked EHR biobank (e.g. All of Us, eMERGE, or UK Biobank — the ICU-centric MIMIC lacks linked germline DNA and is confounded by sepsis, so it can prototype the phenotype logic but not validate it), execute the fever_exacerbated_cav1.2 case-finding query — new ventricular arrhythmia / QT-prolongation event or new seizure shortly after a documented febrile episode, in patients without prior such events — and test whether the identified cohort is enriched for rare/likely-pathogenic CACNA1C variants relative to matched controls. A positive result would support the hypothesis that fever unmasks latent CACNA1C-spectrum disease and validate the query as a case-finding tool.

Decision criterion

Significant enrichment of rare/likely-pathogenic CACNA1C variants in the fever-associated arrhythmia/seizure cohort versus matched controls.

Supporting outcome

Fever acutely unmasks arrhythmia/seizure susceptibility in human CACNA1C carriers; the EHR query is a valid latent-case-finding tool.

Refuting outcome

No CACNA1C enrichment, indicating the zebrafish fever effect does not translate to a detectable human EHR signal (or the query lacks specificity).

Human iPSC/organ-on-chip and in-silico hyperthermia challenge of CACNA1C G406R

iPSC/organ-on-chip and in-silico temperature-challenge assay

exp_ts_fever_ipsc_nam_challenge

Directly test whether the zebrafish fever effect is intrinsic to human CACNA1C-mutant cells, using New Approach Methodologies rather than an animal model. Subject patient-derived (and isogenic CRISPR-corrected control) human iPSC-derived cardiomyocytes and cortical/GABAergic neurons — and a cardiac microtissue/heart-on-chip — to a controlled hyperthermia challenge (raising temperature from 37 to ~40 degrees C), and pair this with an in-silico human ventricular action-potential model carrying a temperature-dependent CaV1.2 formulation. Timothy syndrome already has human iPSC evidence for the baseline mechanism (PMID:21307850 cardiomyocytes, PMID:22120178 neurons), so adding a temperature arm to those same NAM platforms is the lowest-inferential -distance human-relevant test of the fever hypothesis and the natural way to close the zebrafish-to-human gap this discussion raises.

Model systems

CACNA1C G406R human iPSC-derived cardiomyocytes

Patient-derived and isogenic CRISPR-corrected iPSC-cardiomyocytes; assess temperature-dependent action-potential and calcium-handling changes.

IPSC DERIVED MODEL

human NCBITaxon:9606

CACNA1C G406R human iPSC-derived cortical/GABAergic neuronal network

iPSC-derived neuronal networks on multi-electrode arrays to test temperature-dependent hyperexcitability and seizure-like bursting.

IPSC DERIVED MODEL

human NCBITaxon:9606

Cardiac microtissue / heart-on-chip

3D engineered human cardiac microtissue to test temperature-dependent arrhythmic behavior in a tissue-level NAM.

ORGAN ON CHIP namo:OrganOnChip link

human NCBITaxon:9606

In-silico human ventricular action-potential model

Computational human ventricular AP model with a temperature-dependent CaV1.2 formulation to predict fever-induced action-potential prolongation and early afterdepolarizations.

OTHER

Perturbations

Controlled hyperthermia (fever) challenge

pathophysiology#Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold

Raise culture/model temperature from 37 to ~40 degrees C, comparing mutant with isogenic-corrected controls.

Readouts

Temperature-dependent APD prolongation and early afterdepolarizations

pathophysiology#Ventricular tachyarrhythmia (torsade de pointes)

Action-potential duration, persistent L-type calcium current, and EAD frequency in cardiomyocytes / microtissue at febrile versus normothermic temperature.

Temperature-dependent network hyperexcitability

pathophysiology#Fever-associated increased seizure susceptibility

Multi-electrode-array burst rate and network synchrony in iPSC-neurons at febrile versus normothermic temperature.

Decision criterion

A temperature-dependent increase in APD/EAD (cardiomyocytes/microtissue) and network hyperexcitability (neurons) in CACNA1C G406R models but not in isogenic-corrected controls, reproduced in silico.

Supporting outcome

The fever effect is intrinsic to human CACNA1C-mutant cells, translating the zebrafish finding to human biology and raising the hypothesis from MODEL_SYSTEM_EXTRAPOLATION toward a human-validated mechanism.

Refuting outcome

No temperature dependence in human iPSC/organ-on-chip or in-silico models, indicating the zebrafish fever effect may be species-specific and not human-relevant.

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Pathophysiology

10

CACNA1C gain-of-function with impaired Cav1.2 inactivation

Activating CACNA1C variants impair voltage-dependent inactivation of the Cav1.2 L-type calcium channel, causing maintained inward calcium current in excitable cells. This persistent calcium influx is the upstream lesion that links the cardiac, developmental, and neurobehavioral manifestations of Timothy syndrome.

cardiomyocyte CL:0000746

CACNA1C hgnc:1390

voltage-gated calcium channel activity GO:0005245 ↑ INCREASED

Downstream

Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate Persistent inward calcium current prolongs ventricular action potentials and destabilizes cardiomyocyte calcium handling.

Abnormal cortical projection neuron differentiation Persistent mutant channel activity perturbs calcium-dependent gene expression and projection-neuron differentiation during cortical development.

Increased cortical catecholamine synthesis Persistent mutant channel activity drives abnormal tyrosine hydroxylase expression and excess catecholamine production in cortical neurons.

Show evidence (1 reference)

PMID:15454078 SUPPORT In Vitro

"Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation."

Direct functional evidence that the canonical Timothy syndrome variant is a Cav1.2 gain-of-function allele with impaired inactivation.

Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate

In cardiomyocytes, impaired Cav1.2 inactivation produces excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients. These electrophysiologic abnormalities create the substrate for severe QT prolongation, ventricular fibrillation, and sudden death.

cardiomyocyte CL:0000746

membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED cardiac muscle contraction GO:0060048 ↕ DYSREGULATED

heart UBERON:0000948

Downstream

Early afterdepolarizations and arrhythmogenic substrate Prolonged ventricular action potentials and dysregulated calcium handling promote afterdepolarization-driven triggered activity and regional dispersion of repolarization.

Show evidence (2 references)

PMID:21307850 SUPPORT In Vitro

"Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells."

Human iPSC-derived cardiomyocytes directly recapitulate the abnormal ventricular electrophysiology expected from Timothy syndrome.

PMID:15454078 SUPPORT In Vitro

"In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder."

Summarizes the cardiac mechanism linking persistent Cav1.2 current to malignant arrhythmia risk in Timothy syndrome.

Early afterdepolarizations and arrhythmogenic substrate

The markedly prolonged action potential produced by non-inactivating Cav1.2 current, together with abnormal calcium transients, favors early and delayed afterdepolarizations and heterogeneous repolarization across the ventricular wall. In Timothy syndrome iPSC-derived ventricular cardiomyocytes this manifests as action potentials roughly three times longer than control and frequent depolarizing events resembling delayed afterdepolarizations, creating the tissue-level substrate for triggered ventricular arrhythmia.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL cardiac conduction GO:0061337 ↕ DYSREGULATED

heart UBERON:0000948

Downstream

Ventricular tachyarrhythmia (torsade de pointes) Triggered beats arising on the dispersed-repolarization substrate initiate torsade de pointes and polymorphic ventricular tachyarrhythmia.

Show evidence (2 references)

PMID:21307850 SUPPORT In Vitro

"ventricular-like myocytes from TS patients had APs that were three times as long as those of control cells"

Human iPSC-derived ventricular cardiomyocytes show the markedly prolonged action potential that underlies the arrhythmogenic substrate in Timothy syndrome.

PMID:21307850 SUPPORT In Vitro

"These depolarizations were similar to the delayed after depolarizations (DADs) that arise following ectopic release of Ca2+ from the SR and which are associated with cardiac arrhythmias"

The same iPSC cardiomyocytes exhibit afterdepolarization-like triggered events that constitute the arrhythmogenic substrate downstream of delayed repolarization.

Ventricular tachyarrhythmia (torsade de pointes)

Afterdepolarization-triggered activity on the prolonged-repolarization substrate initiates malignant ventricular tachyarrhythmia — torsade de pointes and ventricular fibrillation — that abolishes effective cardiac output and accounts for aborted cardiac arrest and sudden death in Timothy syndrome.

cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Long QT interval and sudden cardiac death susceptibility Sustained ventricular tachyarrhythmia compromises cardiac output, causing aborted cardiac arrest and sudden death and defining the clinical QT/sudden death phenotype.

Show evidence (2 references)

PMID:21307850 SUPPORT In Vitro

"it is difficult to link these features to the Torsade de Points and to ventricular fibrillations in TS patients"

The authors connect the cellular afterdepolarization and prolonged-AP phenotypes to the torsade de pointes and ventricular fibrillation observed clinically in Timothy syndrome patients.

PMID:30067485 SUPPORT Human Clinical

"Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia."

International cohort evidence that ventricular fibrillation is the malignant tachyarrhythmia mediating sudden death in Timothy syndrome.

Abnormal cortical projection neuron differentiation

In the developing cortex, persistent mutant Cav1.2 activity alters calcium signaling, activity-dependent gene expression, and cortical projection neuron differentiation. This includes reduced SATB2-positive callosal projection neuron abundance and excess CTIP2-positive neurons.

neuron CL:0000540

regulation of neuron differentiation GO:0045664 ↕ DYSREGULATED

brain UBERON:0000955

Downstream

Neurodevelopmental phenotype Abnormal cortical projection-neuron differentiation contributes to developmental delay and autistic behavior.

Show evidence (2 references)

PMID:22120178 SUPPORT In Vitro

"Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons."

Human iPSC-derived neurons show the core calcium-signaling and cortical differentiation defects linked to the neurodevelopmental phenotype.

PMID:31868578 SUPPORT In Vitro

"In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons."

Refines the cortical differentiation defect to a specific shift in projection-neuron fate downstream of mutant Cav1.2 signaling.

Increased cortical catecholamine synthesis

In cortical neurons, persistent mutant Cav1.2 activity dysregulates activity-dependent gene expression, increases tyrosine hydroxylase expression, and drives excess norepinephrine and dopamine production.

neuron CL:0000540

neurotransmitter secretion GO:0007269 ↑ INCREASED

brain UBERON:0000955

Downstream

Neurodevelopmental phenotype Excess catecholamine production likely contributes to autistic behavior and broader developmental dysfunction.

Show evidence (1 reference)

PMID:22120178 SUPPORT In Vitro

"In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine."

Human iPSC-derived neurons show that mutant Cav1.2 signaling increases catecholamine biosynthesis and release-related output downstream of tyrosine hydroxylase dysregulation.

Long QT interval and sudden cardiac death susceptibility

The dominant clinical cardiac phenotype is severe QT prolongation with a high risk of aborted cardiac arrest, ventricular fibrillation, and sudden death. Events may be precipitated by physiologic stressors including general anesthesia and hypoglycemia.

Downstream

Prolonged QT Interval Delayed ventricular repolarization manifests clinically as a prolonged QT interval.

Sudden Cardiac Death Severe QT prolongation and malignant ventricular arrhythmia susceptibility can culminate in sudden cardiac death.

Show evidence (2 references)

PMID:30067485 SUPPORT Human Clinical

"The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms."

Confirms that severe QT prolongation is the defining cardiac phenotype in a modern international cohort.

PMID:30067485 SUPPORT Human Clinical

"Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia."

Direct cohort evidence that ventricular fibrillation and sudden death are major clinical outcomes in Timothy syndrome.

Neurodevelopmental phenotype

Timothy syndrome commonly includes developmental delay and autistic behavior, reflecting the effects of persistent Cav1.2 activity on cortical differentiation and calcium-dependent neuronal signaling.

Downstream

Autistic Behavior The neurodevelopmental phenotype includes autistic behavior in classical Timothy syndrome.

Global Developmental Delay The neurodevelopmental phenotype includes global developmental delay in classical Timothy syndrome.

Show evidence (1 reference)

PMID:41333400 SUPPORT Other

"Timothy Syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism, and syndactyly or hip dysplasia."

Current consensus explicitly includes developmental delay and autism as core features of the classical Timothy syndrome phenotype.

Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold

Elevated body temperature activates the CaV1.2 L-type calcium channel. Superimposed on the CACNA1C gain-of-function lesion, fever is hypothesized to further augment the persistent inward calcium current, acutely lowering the threshold for both ventricular arrhythmia and seizures. In a zebrafish cacna1c model this was sufficient to elicit arrhythmia and seizure-like behavior even in overtly normal heterozygotes, framing fever as an acute, modifiable exacerbating factor rather than a fixed trait. This node and its downstream edges are part of the emerging fever_exacerbated_cav1.2 hypothesis.

Fever/elevated body temperature lowers the threshold for CaV1.2-driven arrhythmia and seizures

CACNA1C hgnc:1390

cellular response to heat GO:0034605 ↑ INCREASED

voltage-gated calcium channel activity GO:0005245 ↑ INCREASED

Downstream

Ventricular tachyarrhythmia (torsade de pointes) Fever-driven enhancement of mutant CaV1.2 current lowers the threshold for triggered ventricular tachyarrhythmia.

Fever-associated increased seizure susceptibility Fever-driven enhancement of mutant CaV1.2 current, together with neuropeptide dysregulation, lowers the seizure threshold.

Show evidence (2 references)

PMID:42426269 SUPPORT Other

"fever, known to activate CaV1.2 channels, may exacerbate TS, yet its impact is poorly understood"

Establishes the premise that fever activates CaV1.2, the channel mutated in Timothy syndrome.

PMID:42426269 SUPPORT Model Organism

"elevated water temperature elicited arrhythmia and seizure-like behavior even in overtly normal heterozygotes, implicating fever as a modifiable risk"

Zebrafish model shows temperature is sufficient to trigger both arrhythmia and seizure-like activity in otherwise-normal heterozygotes.

Fever-associated increased seizure susceptibility

Elevated temperature and persistent mutant CaV1.2 activity lower the seizure threshold. In the zebrafish model, mutants showed increased susceptibility to pentylenetetrazole-induced seizures and temperature-elicited seizure-like behavior, accompanied by dysregulated expression of neuropeptides including bdnf and vgf and abnormal GABAergic neuron development — candidate mediators of the lowered seizure threshold. Human validity of this fever-exacerbation arm is not yet established.

Fever/elevated body temperature lowers the threshold for CaV1.2-driven arrhythmia and seizures

GABAergic neuron CL:0000617

brain UBERON:0000955

Downstream

Seizures Lowered seizure threshold manifests clinically as seizures, an established feature of Timothy syndrome that may be precipitated by fever.

Show evidence (2 references)

PMID:42426269 SUPPORT Model Organism

"These fish exhibited arrhythmias, increased susceptibility to pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy and abnormal GABAergic neuron development"

Zebrafish cacna1c mutants show increased chemically-induced seizure susceptibility and abnormal GABAergic development.

PMID:42426269 SUPPORT Model Organism

"Transcriptomic analysis revealed dysregulated expression of neuropeptides including bdnf and vgf"

Identifies BDNF and VGF neuropeptide dysregulation as candidate molecular mediators of altered neuronal excitability.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 3

Prolonged QT Interval HP:0001657

Show evidence (1 reference)

PMID:30067485 SUPPORT Human Clinical

"The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms."

Modern cohort study confirming QT prolongation as the defining cardiac phenotype.

Congenital Heart Disease Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:15454078 SUPPORT Human Clinical

"Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism."

Original clinical series documents congenital heart disease as part of the syndrome.

Sudden Cardiac Death HP:0001645

Show evidence (1 reference)

PMID:30067485 SUPPORT Human Clinical

"Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia."

International cohort evidence showing that sudden death remains a major clinical outcome in Timothy syndrome.

Limbs 1

Syndactyly HP:0001159

Show evidence (1 reference)

PMID:15454078 SUPPORT Human Clinical

"Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism."

The original syndrome description identifies webbing of fingers and toes, supporting syndactyly as a canonical feature.

Metabolism 1

Hypoglycemia HP:0001943

Show evidence (1 reference)

PMID:15454078 SUPPORT Human Clinical

"Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism."

The original clinical series identifies intermittent hypoglycemia as a recurrent part of the syndrome.

Nervous System 3

Autistic Behavior HP:0000729

Show evidence (1 reference)

PMID:41333400 SUPPORT Other

"Timothy Syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism, and syndactyly or hip dysplasia."

Recent consensus explicitly recognizes autism within the classical Timothy syndrome phenotype.

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:41333400 SUPPORT Other

"Timothy Syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism, and syndactyly or hip dysplasia."

Current consensus identifies developmental delay as part of the classical neurodevelopmental presentation.

Seizures HP:0001250

Show evidence (2 references)

PMID:42426269 SUPPORT Other

"Timothy syndrome (TS) is a multisystem disorder with autistic-like features, seizures and life-threatening arrhythmias"

States that seizures are an established feature of the human Timothy syndrome phenotype.

PMID:42426269 SUPPORT Model Organism

"These fish exhibited arrhythmias, increased susceptibility to pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy and abnormal GABAergic neuron development"

Zebrafish cacna1c model recapitulates increased seizure susceptibility, providing mechanistic support for the seizure phenotype.

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Genetic Associations

1

CACNA1C (Pathogenic Variants)

Gene: CACNA1C hgnc:1390

Show evidence (1 reference)

CGGV:assertion_a1fc2dfc-d200-40d0-9cd6-421276578e6e-2023-04-14T020000.000Z SUPPORT Other

ClinGen classifies the CACNA1C-Timothy syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

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Medical Actions

2

Beta-Blocker Therapy

Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986

Beta-blockers are standard first-line antiarrhythmic therapy in Timothy syndrome to blunt adrenergic triggering of malignant ventricular arrhythmias.

Mechanism Target:

INHIBITS Early afterdepolarizations and arrhythmogenic substrate — Beta-blockers blunt sympathetic adrenergic drive that triggers early afterdepolarizations in the prolonged Cav1.2-dependent action potential, reducing catecholamine-provoked arrhythmia.

INHIBITS Ventricular tachyarrhythmia (torsade de pointes) — By reducing adrenergic triggers, beta-blockers lower the frequency of torsade de pointes and sudden cardiac events in Timothy syndrome.

Show evidence (1 reference)

PMID:30067485 SUPPORT Human Clinical

"All patients were treated with beta-blockers"

Documents universal beta-blocker use in the modern international Timothy syndrome cohort.

Implantable Cardioverter-Defibrillator (ICD)

Action: ICD implantation Ontology label: Surgical Procedure NCIT:C15329

ICD placement is commonly used in high-risk patients because severe ventricular arrhythmias and aborted cardiac arrest remain common despite pharmacotherapy.

Mechanism Target:

MODULATES Ventricular tachyarrhythmia (torsade de pointes) — ICD detects and delivers defibrillation shocks to terminate malignant ventricular arrhythmias but does not address the upstream CACNA1C gain-of-function or prolonged repolarization.

Show evidence (1 reference)

PMID:30067485 SUPPORT Human Clinical

"13 patients (76%) were also treated with an implantable defibrillator."

High ICD utilization in the international cohort reflects the severe arrhythmic risk of Timothy syndrome.

{ }

Source YAML

click to show

name: Timothy Syndrome
creation_date: "2026-04-12T00:00:00Z"
category: Mendelian
description: >-
  Timothy syndrome is a rare CACNA1C-associated multisystem channelopathy caused
  by gain-of-function variants in the Cav1.2 L-type calcium channel, classically
  the recurrent G406R variant in alternatively spliced exon 8A and related exon
  8 variants. The syndrome is defined by marked QT prolongation with
  life-threatening ventricular arrhythmia and is frequently accompanied by
  syndactyly, congenital heart disease, intermittent hypoglycemia,
  developmental delay, and autistic behavior. The core mechanism is impaired
  voltage-dependent channel inactivation, which produces maintained inward
  calcium current, delayed cardiomyocyte repolarization, and abnormal
  calcium-dependent differentiation programs in the developing cortex.
disease_term:
  preferred_term: Timothy syndrome
  term:
    id: MONDO:0010979
    label: Timothy syndrome
definitions:
- name: Clinical disease framing for Timothy syndrome
  definition_type: CASE_DEFINITION
  description: >-
    Timothy syndrome is the classical syndromic CACNA1C gain-of-function
    phenotype defined by prolonged QT interval with malignant arrhythmia plus
    characteristic extracardiac developmental features, especially syndactyly
    and neurodevelopmental abnormalities.
  scope: Classical MONDO disease framing for the syndromic CACNA1C channelopathy
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present Timothy syndrome, a novel disorder characterized by
      multiorgan dysfunction including lethal arrhythmias, webbing of fingers
      and toes, congenital heart disease, immune deficiency, intermittent
      hypoglycemia, cognitive abnormalities, and autism.
    explanation: >-
      Landmark clinical report defining the classical multisystem Timothy
      syndrome phenotype.
  - reference: PMID:41333400
    reference_title: >-
      Timothy Syndrome and CACNA1C-Related Disorder: First International
      Language and Management Guidelines Consensus Statement.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We formalise the language around syndromic presentations linked to CACNA1C
      variants, reassert and demarcate the classical Timothy Syndrome phenotype,
      and define a new syndrome, CACNA1C-Related Disorder.
    explanation: >-
      Recent consensus supports retaining a classical Timothy syndrome disease
      framing while acknowledging a broader CACNA1C-related disorder spectrum.
- name: Molecular definition for Timothy syndrome
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Molecularly, this entry captures heterozygous activating CACNA1C variants
    that impair Cav1.2 voltage-dependent inactivation and create persistent
    inward calcium current.
  scope: Molecular anchoring of classical CACNA1C-related Timothy syndrome
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional expression reveals that G406R produces maintained inward
      Ca(2+) currents by causing nearly complete loss of voltage-dependent
      channel inactivation.
    explanation: >-
      Defines the core gain-of-function mechanism of Timothy syndrome at the
      channel level.
- name: >-
    Fever-associated arrhythmia/seizure case-finding query for latent CACNA1C
    carriers
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: MECHANISTIC_HYPOTHESIS
  validation_status:
    status: PROPOSED
    rationale: >-
      Drafted from the zebrafish fever-exacerbation result; never executed
      against a human EHR/OMOP dataset, so no PPV/sensitivity is characterized.
  attaches_to:
  - pathophysiology#Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold
  description: >-
    Proposed EHR/OMOP case-finding query: identify individuals with a new
    ventricular arrhythmia / QT-prolongation event or a new seizure within a
    short window after a documented febrile episode, absent a prior such event,
    as candidate latent or mild CACNA1C-spectrum cases. The query operationalizes
    the emerging fever_exacerbated_cav1.2 hypothesis (fever activates CaV1.2 and
    can unmask arrhythmia/seizures even in overtly normal carriers); a positive
    yield is itself partial evidence for that hypothesis.
  scope: >-
    EHR/OMOP case-finding; HYPOTHESIS-GENERATING, NOT a validated diagnostic or
    consensus phenotype algorithm. Predicated on an unproven mechanism
    (fever_exacerbated_cav1.2) whose human validity is an open question.
  criteria_sets:
  - name: Febrile-onset rhythm disturbance or seizure
    description: >-
      Documented fever (temperature or febrile-illness diagnosis code) followed
      within a short window (e.g. days) by a NEW ventricular arrhythmia /
      long-QT event or a new seizure, with no prior arrhythmia/seizure history.
      Temporal window and code sets to be specified at implementation.
    inclusion_criteria:
    - preferred_term: Documented febrile episode
      description: Elevated body temperature or a febrile-illness diagnosis code (index exposure).
    - preferred_term: New post-fever arrhythmia or seizure
      description: >-
        First ventricular arrhythmia / QT-prolongation event or first seizure
        occurring shortly after the febrile episode.
    exclusion_criteria:
    - preferred_term: Pre-existing arrhythmia or epilepsy
      description: >-
        Prior history of the same event type, which would confound the
        fever-provoked interpretation.
  evidence:
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      elevated water temperature elicited arrhythmia and seizure-like behavior
      even in overtly normal heterozygotes, implicating fever as a modifiable
      risk
    explanation: >-
      Model-system basis for the query: temperature elicited arrhythmia and
      seizure-like behavior in phenotypically normal cacna1c heterozygotes,
      motivating a search for analogous latent human cases.
  notes: >-
    Hypothesis-based, unvalidated case-finding query — not a consensus or
    gold-standard-validated phenotype algorithm. Its epistemic status is carried
    structurally by derivation_basis (MECHANISTIC_HYPOTHESIS), the
    validation_status object (PROPOSED), and attaches_to the fever-trigger
    pathophysiology node, so the hypothesis basis is inferred from the pathograph
    (fever_exacerbated_cav1.2). See monarch-initiative/dismech#6245.
synonyms:
- LQT8
- long QT syndrome 8
- long QT syndrome with syndactyly
- CACNA1C-related Timothy syndrome
parents:
- Cardiac Arrhythmia
- Channelopathy
- Neurodevelopmental Disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Timothy syndrome is mechanistically an autosomal dominant gain-of-function
    disorder, although most classical cases reported so far have arisen de novo.
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In every case, Timothy syndrome results from the identical, de novo
      Ca(V)1.2 missense mutation G406R.
    explanation: >-
      Recurrent heterozygous de novo pathogenic variants support a dominant
      disease architecture with most observed cases being sporadic.
mechanistic_hypotheses:
- hypothesis_group_id: fever_exacerbated_cav1.2
  hypothesis_label: >-
    Fever/elevated body temperature lowers the threshold for CaV1.2-driven
    arrhythmia and seizures
  status: EMERGING
  description: >-
    Elevated body temperature activates the CaV1.2 L-type calcium channel and is
    hypothesized to augment the mutant persistent inward calcium current, so
    febrile episodes may acutely unmask ventricular arrhythmia and lower the
    seizure threshold — even in CACNA1C carriers who are overtly normal at
    baseline. This frames fever as a modifiable risk factor and, at a
    population level, as a candidate signal for scanning electronic health
    records for latent or mild CACNA1C-spectrum cases (e.g. a new rhythm
    disturbance or seizure temporally following a documented fever). The
    hypothesis is currently supported by a zebrafish cacna1c model; its validity
    in human patients is an open question (see the linked HUMAN_MODEL_MISMATCH
    discussion). Downstream causal edges that belong to this hypothesis opt in
    via hypothesis_groups: [fever_exacerbated_cav1.2].
  evidence:
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      elevated water temperature elicited arrhythmia and seizure-like behavior
      even in overtly normal heterozygotes, implicating fever as a modifiable
      risk
    explanation: >-
      In a zebrafish cacna1c Timothy-syndrome model, raising temperature
      elicited arrhythmia and seizure-like behavior even in phenotypically
      normal heterozygotes, directly motivating the fever-exacerbation
      hypothesis.
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      fever, known to activate CaV1.2 channels, may exacerbate TS, yet its
      impact is poorly understood
    explanation: >-
      States the biophysical premise (fever activates CaV1.2) and that its
      impact on Timothy syndrome is not yet characterized in patients.
pathophysiology:
- name: CACNA1C gain-of-function with impaired Cav1.2 inactivation
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    Activating CACNA1C variants impair voltage-dependent inactivation of the
    Cav1.2 L-type calcium channel, causing maintained inward calcium current in
    excitable cells. This persistent calcium influx is the upstream lesion that
    links the cardiac, developmental, and neurobehavioral manifestations of
    Timothy syndrome.
  gene:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: voltage-gated calcium channel activity
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: INCREASED
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional expression reveals that G406R produces maintained inward
      Ca(2+) currents by causing nearly complete loss of voltage-dependent
      channel inactivation.
    explanation: >-
      Direct functional evidence that the canonical Timothy syndrome variant is
      a Cav1.2 gain-of-function allele with impaired inactivation.
  downstream:
  - target: Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate
    description: >-
      Persistent inward calcium current prolongs ventricular action potentials
      and destabilizes cardiomyocyte calcium handling.
  - target: Abnormal cortical projection neuron differentiation
    description: >-
      Persistent mutant channel activity perturbs calcium-dependent gene
      expression and projection-neuron differentiation during cortical
      development.
  - target: Increased cortical catecholamine synthesis
    description: >-
      Persistent mutant channel activity drives abnormal tyrosine hydroxylase
      expression and excess catecholamine production in cortical neurons.
- name: Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: central_effector
  description: >-
    In cardiomyocytes, impaired Cav1.2 inactivation produces excess calcium
    influx, prolonged action potentials, irregular electrical activity, and
    abnormal calcium transients. These electrophysiologic abnormalities create
    the substrate for severe QT prolongation, ventricular fibrillation, and
    sudden death.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DYSREGULATED
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:21307850
    reference_title: >-
      Using induced pluripotent stem cells to investigate cardiac phenotypes in
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Electrophysiological recording and calcium (Ca(2+)) imaging studies of
      these cells revealed irregular contraction, excess Ca(2+) influx,
      prolonged action potentials, irregular electrical activity and abnormal
      calcium transients in ventricular-like cells.
    explanation: >-
      Human iPSC-derived cardiomyocytes directly recapitulate the abnormal
      ventricular electrophysiology expected from Timothy syndrome.
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In the heart, prolonged Ca(2+) current delays cardiomyocyte
      repolarization and increases risk of arrhythmia, the ultimate cause of
      death in this disorder.
    explanation: >-
      Summarizes the cardiac mechanism linking persistent Cav1.2 current to
      malignant arrhythmia risk in Timothy syndrome.
  downstream:
  - target: Early afterdepolarizations and arrhythmogenic substrate
    description: >-
      Prolonged ventricular action potentials and dysregulated calcium handling
      promote afterdepolarization-driven triggered activity and regional
      dispersion of repolarization.
- name: Early afterdepolarizations and arrhythmogenic substrate
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    The markedly prolonged action potential produced by non-inactivating Cav1.2
    current, together with abnormal calcium transients, favors early and delayed
    afterdepolarizations and heterogeneous repolarization across the ventricular
    wall. In Timothy syndrome iPSC-derived ventricular cardiomyocytes this
    manifests as action potentials roughly three times longer than control and
    frequent depolarizing events resembling delayed afterdepolarizations,
    creating the tissue-level substrate for triggered ventricular arrhythmia.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:21307850
    reference_title: >-
      Using induced pluripotent stem cells to investigate cardiac phenotypes in
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ventricular-like myocytes from TS patients had APs that were three times
      as long as those of control cells
    explanation: >-
      Human iPSC-derived ventricular cardiomyocytes show the markedly prolonged
      action potential that underlies the arrhythmogenic substrate in Timothy
      syndrome.
  - reference: PMID:21307850
    reference_title: >-
      Using induced pluripotent stem cells to investigate cardiac phenotypes in
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These depolarizations were similar to the delayed after depolarizations
      (DADs) that arise following ectopic release of Ca2+ from the SR and which
      are associated with cardiac arrhythmias
    explanation: >-
      The same iPSC cardiomyocytes exhibit afterdepolarization-like triggered
      events that constitute the arrhythmogenic substrate downstream of delayed
      repolarization.
  downstream:
  - target: Ventricular tachyarrhythmia (torsade de pointes)
    description: >-
      Triggered beats arising on the dispersed-repolarization substrate initiate
      torsade de pointes and polymorphic ventricular tachyarrhythmia.
- name: Ventricular tachyarrhythmia (torsade de pointes)
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  description: >-
    Afterdepolarization-triggered activity on the prolonged-repolarization
    substrate initiates malignant ventricular tachyarrhythmia — torsade de
    pointes and ventricular fibrillation — that abolishes effective cardiac
    output and accounts for aborted cardiac arrest and sudden death in Timothy
    syndrome.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:21307850
    reference_title: >-
      Using induced pluripotent stem cells to investigate cardiac phenotypes in
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      it is difficult to link these features to the Torsade de Points and to
      ventricular fibrillations in TS patients
    explanation: >-
      The authors connect the cellular afterdepolarization and prolonged-AP
      phenotypes to the torsade de pointes and ventricular fibrillation observed
      clinically in Timothy syndrome patients.
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients died suddenly due to ventricular fibrillation, 2 of whom
      had associated hypoglycemia.
    explanation: >-
      International cohort evidence that ventricular fibrillation is the
      malignant tachyarrhythmia mediating sudden death in Timothy syndrome.
  downstream:
  - target: Long QT interval and sudden cardiac death susceptibility
    description: >-
      Sustained ventricular tachyarrhythmia compromises cardiac output, causing
      aborted cardiac arrest and sudden death and defining the clinical QT/sudden
      death phenotype.
- name: Abnormal cortical projection neuron differentiation
  description: >-
    In the developing cortex, persistent mutant Cav1.2 activity alters calcium
    signaling, activity-dependent gene expression, and cortical projection
    neuron differentiation. This includes reduced SATB2-positive callosal
    projection neuron abundance and excess CTIP2-positive neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of neuron differentiation
    term:
      id: GO:0045664
      label: regulation of neuron differentiation
    modifier: DYSREGULATED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:22120178
    reference_title: >-
      Using iPSC-derived neurons to uncover cellular phenotypes associated with
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cells from these individuals have defects in calcium (Ca(2+)) signaling
      and activity-dependent gene expression. They also show abnormalities in
      differentiation, including decreased expression of genes that are
      expressed in lower cortical layers and in callosal projection neurons.
    explanation: >-
      Human iPSC-derived neurons show the core calcium-signaling and cortical
      differentiation defects linked to the neurodevelopmental phenotype.
  - reference: PMID:31868578
    reference_title: >-
      Aberrant calcium channel splicing drives defects in cortical
      differentiation in Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In iPSC models, the TS mutation reduces the abundance of
      SATB2-expressing cortical projection neurons, leading to excess CTIP2+
      neurons.
    explanation: >-
      Refines the cortical differentiation defect to a specific shift in
      projection-neuron fate downstream of mutant Cav1.2 signaling.
  downstream:
  - target: Neurodevelopmental phenotype
    description: >-
      Abnormal cortical projection-neuron differentiation contributes to
      developmental delay and autistic behavior.
- name: Increased cortical catecholamine synthesis
  description: >-
    In cortical neurons, persistent mutant Cav1.2 activity dysregulates
    activity-dependent gene expression, increases tyrosine hydroxylase
    expression, and drives excess norepinephrine and dopamine production.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neurotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
    modifier: INCREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:22120178
    reference_title: >-
      Using iPSC-derived neurons to uncover cellular phenotypes associated with
      Timothy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, neurons derived from individuals with Timothy syndrome show
      abnormal expression of tyrosine hydroxylase and increased production of
      norepinephrine and dopamine.
    explanation: >-
      Human iPSC-derived neurons show that mutant Cav1.2 signaling increases
      catecholamine biosynthesis and release-related output downstream of
      tyrosine hydroxylase dysregulation.
  downstream:
  - target: Neurodevelopmental phenotype
    description: >-
      Excess catecholamine production likely contributes to autistic behavior
      and broader developmental dysfunction.
- name: Long QT interval and sudden cardiac death susceptibility
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  description: >-
    The dominant clinical cardiac phenotype is severe QT prolongation with a
    high risk of aborted cardiac arrest, ventricular fibrillation, and sudden
    death. Events may be precipitated by physiologic stressors including general
    anesthesia and hypoglycemia.
  evidence:
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The syndrome is characterized by multisystem abnormalities consisting of
      QT prolongation, congenital heart defects, syndactyly, facial
      dysmorphism, and neurological symptoms.
    explanation: >-
      Confirms that severe QT prolongation is the defining cardiac phenotype in
      a modern international cohort.
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients died suddenly due to ventricular fibrillation, 2 of whom
      had associated hypoglycemia.
    explanation: >-
      Direct cohort evidence that ventricular fibrillation and sudden death are
      major clinical outcomes in Timothy syndrome.
  downstream:
  - target: Prolonged QT Interval
    description: Delayed ventricular repolarization manifests clinically as a prolonged QT interval.
    causal_link_type: DIRECT
  - target: Sudden Cardiac Death
    description: Severe QT prolongation and malignant ventricular arrhythmia susceptibility can culminate in sudden cardiac death.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ventricular tachyarrhythmia
    - ventricular fibrillation
- name: Neurodevelopmental phenotype
  description: >-
    Timothy syndrome commonly includes developmental delay and autistic
    behavior, reflecting the effects of persistent Cav1.2 activity on cortical
    differentiation and calcium-dependent neuronal signaling.
  evidence:
  - reference: PMID:41333400
    reference_title: >-
      Timothy Syndrome and CACNA1C-Related Disorder: First International
      Language and Management Guidelines Consensus Statement.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Timothy Syndrome is a multisystemic genetic disorder, classically
      characterised by prolonged QT interval and subsequent cardiac arrhythmias,
      neurodevelopmental disorders including developmental delay and autism, and
      syndactyly or hip dysplasia.
    explanation: >-
      Current consensus explicitly includes developmental delay and autism as
      core features of the classical Timothy syndrome phenotype.
  downstream:
  - target: Autistic Behavior
    description: The neurodevelopmental phenotype includes autistic behavior in classical Timothy syndrome.
    causal_link_type: DIRECT
  - target: Global Developmental Delay
    description: The neurodevelopmental phenotype includes global developmental delay in classical Timothy syndrome.
    causal_link_type: DIRECT
- name: Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold
  role: trigger
  description: >-
    Elevated body temperature activates the CaV1.2 L-type calcium channel.
    Superimposed on the CACNA1C gain-of-function lesion, fever is hypothesized to
    further augment the persistent inward calcium current, acutely lowering the
    threshold for both ventricular arrhythmia and seizures. In a zebrafish
    cacna1c model this was sufficient to elicit arrhythmia and seizure-like
    behavior even in overtly normal heterozygotes, framing fever as an acute,
    modifiable exacerbating factor rather than a fixed trait. This node and its
    downstream edges are part of the emerging fever_exacerbated_cav1.2
    hypothesis.
  gene:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  molecular_functions:
  - preferred_term: voltage-gated calcium channel activity
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: cellular response to heat
    term:
      id: GO:0034605
      label: cellular response to heat
    modifier: INCREASED
  evidence:
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      fever, known to activate CaV1.2 channels, may exacerbate TS, yet its
      impact is poorly understood
    explanation: >-
      Establishes the premise that fever activates CaV1.2, the channel mutated in
      Timothy syndrome.
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      elevated water temperature elicited arrhythmia and seizure-like behavior
      even in overtly normal heterozygotes, implicating fever as a modifiable
      risk
    explanation: >-
      Zebrafish model shows temperature is sufficient to trigger both arrhythmia
      and seizure-like activity in otherwise-normal heterozygotes.
  downstream:
  - target: Ventricular tachyarrhythmia (torsade de pointes)
    description: >-
      Fever-driven enhancement of mutant CaV1.2 current lowers the threshold for
      triggered ventricular tachyarrhythmia.
    hypothesis_groups:
    - fever_exacerbated_cav1.2
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - augmented persistent inward calcium current
    - early afterdepolarizations
  - target: Fever-associated increased seizure susceptibility
    description: >-
      Fever-driven enhancement of mutant CaV1.2 current, together with
      neuropeptide dysregulation, lowers the seizure threshold.
    hypothesis_groups:
    - fever_exacerbated_cav1.2
- name: Fever-associated increased seizure susceptibility
  role: effector
  description: >-
    Elevated temperature and persistent mutant CaV1.2 activity lower the seizure
    threshold. In the zebrafish model, mutants showed increased susceptibility to
    pentylenetetrazole-induced seizures and temperature-elicited seizure-like
    behavior, accompanied by dysregulated expression of neuropeptides including
    bdnf and vgf and abnormal GABAergic neuron development — candidate mediators
    of the lowered seizure threshold. Human validity of this fever-exacerbation
    arm is not yet established.
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These fish exhibited arrhythmias, increased susceptibility to
      pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy
      and abnormal GABAergic neuron development
    explanation: >-
      Zebrafish cacna1c mutants show increased chemically-induced seizure
      susceptibility and abnormal GABAergic development.
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Transcriptomic analysis revealed dysregulated expression of neuropeptides
      including bdnf and vgf
    explanation: >-
      Identifies BDNF and VGF neuropeptide dysregulation as candidate molecular
      mediators of altered neuronal excitability.
  downstream:
  - target: Seizures
    description: >-
      Lowered seizure threshold manifests clinically as seizures, an established
      feature of Timothy syndrome that may be precipitated by fever.
    hypothesis_groups:
    - fever_exacerbated_cav1.2
phenotypes:
- category: Cardiovascular
  name: Prolonged QT Interval
  description: >-
    Severe prolongation of ventricular repolarization on ECG is the hallmark
    cardiac phenotype of Timothy syndrome and underlies its malignant arrhythmia
    risk.
  phenotype_term:
    preferred_term: prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The syndrome is characterized by multisystem abnormalities consisting of
      QT prolongation, congenital heart defects, syndactyly, facial
      dysmorphism, and neurological symptoms.
    explanation: >-
      Modern cohort study confirming QT prolongation as the defining cardiac
      phenotype.
- category: Cardiovascular
  name: Congenital Heart Disease
  description: >-
    Structural congenital heart disease can accompany the arrhythmia phenotype,
    contributing to the multisystem presentation.
  phenotype_term:
    preferred_term: congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present Timothy syndrome, a novel disorder characterized by
      multiorgan dysfunction including lethal arrhythmias, webbing of fingers
      and toes, congenital heart disease, immune deficiency, intermittent
      hypoglycemia, cognitive abnormalities, and autism.
    explanation: >-
      Original clinical series documents congenital heart disease as part of the
      syndrome.
- category: Musculoskeletal
  name: Syndactyly
  description: >-
    Cutaneous webbing of fingers and toes is a classic extracardiac feature and
    historically helped define the syndrome.
  phenotype_term:
    preferred_term: syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present Timothy syndrome, a novel disorder characterized by
      multiorgan dysfunction including lethal arrhythmias, webbing of fingers
      and toes, congenital heart disease, immune deficiency, intermittent
      hypoglycemia, cognitive abnormalities, and autism.
    explanation: >-
      The original syndrome description identifies webbing of fingers and toes,
      supporting syndactyly as a canonical feature.
- category: Neurodevelopmental
  name: Autistic Behavior
  description: >-
    Autism spectrum features are a core part of the classical syndromic
    presentation and reflect the neurodevelopmental effects of CACNA1C
    gain-of-function.
  phenotype_term:
    preferred_term: autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:41333400
    reference_title: >-
      Timothy Syndrome and CACNA1C-Related Disorder: First International
      Language and Management Guidelines Consensus Statement.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Timothy Syndrome is a multisystemic genetic disorder, classically
      characterised by prolonged QT interval and subsequent cardiac arrhythmias,
      neurodevelopmental disorders including developmental delay and autism, and
      syndactyly or hip dysplasia.
    explanation: >-
      Recent consensus explicitly recognizes autism within the classical Timothy
      syndrome phenotype.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Developmental delay is common in surviving patients and aligns with the
    cortical differentiation defects seen in human cellular models.
  phenotype_term:
    preferred_term: global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41333400
    reference_title: >-
      Timothy Syndrome and CACNA1C-Related Disorder: First International
      Language and Management Guidelines Consensus Statement.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Timothy Syndrome is a multisystemic genetic disorder, classically
      characterised by prolonged QT interval and subsequent cardiac arrhythmias,
      neurodevelopmental disorders including developmental delay and autism, and
      syndactyly or hip dysplasia.
    explanation: >-
      Current consensus identifies developmental delay as part of the classical
      neurodevelopmental presentation.
- category: Metabolic
  name: Hypoglycemia
  description: >-
    Intermittent hypoglycemia is a recurrent extracardiac feature and may
    contribute to arrhythmia risk during acute events.
  phenotype_term:
    preferred_term: hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:15454078
    reference_title: >-
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
      including arrhythmia and autism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present Timothy syndrome, a novel disorder characterized by
      multiorgan dysfunction including lethal arrhythmias, webbing of fingers
      and toes, congenital heart disease, immune deficiency, intermittent
      hypoglycemia, cognitive abnormalities, and autism.
    explanation: >-
      The original clinical series identifies intermittent hypoglycemia as a
      recurrent part of the syndrome.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden cardiac death from ventricular fibrillation remains a major outcome
    risk despite modern management.
  phenotype_term:
    preferred_term: sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients died suddenly due to ventricular fibrillation, 2 of whom
      had associated hypoglycemia.
    explanation: >-
      International cohort evidence showing that sudden death remains a major
      clinical outcome in Timothy syndrome.
- category: Neurologic
  name: Seizures
  description: >-
    Seizures are an established feature of the Timothy syndrome phenotype. The
    seizure threshold is hypothesized to be lowered acutely by fever via
    temperature-dependent CaV1.2 activation (see the fever_exacerbated_cav1.2
    mechanistic hypothesis); the fever-provoked component is currently supported
    by a zebrafish model rather than by human data.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Timothy syndrome (TS) is a multisystem disorder with autistic-like
      features, seizures and life-threatening arrhythmias
    explanation: >-
      States that seizures are an established feature of the human Timothy
      syndrome phenotype.
  - reference: PMID:42426269
    reference_title: >-
      Elevated body temperature exacerbates arrhythmia and seizure-like activity
      in a zebrafish model of Timothy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These fish exhibited arrhythmias, increased susceptibility to
      pentylenetetrazole-induced seizures, microcephaly, cerebellar hypotrophy
      and abnormal GABAergic neuron development
    explanation: >-
      Zebrafish cacna1c model recapitulates increased seizure susceptibility,
      providing mechanistic support for the seizure phenotype.
genetic:
- name: CACNA1C
  gene_term:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_a1fc2dfc-d200-40d0-9cd6-421276578e6e-2023-04-14T020000.000Z
    reference_title: "CACNA1C / Timothy syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CACNA1C | HGNC:1390 | Timothy syndrome | MONDO:0010979 | AD | Definitive"
    explanation: ClinGen classifies the CACNA1C-Timothy syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Beta-Blocker Therapy
  description: >-
    Beta-blockers are standard first-line antiarrhythmic therapy in Timothy
    syndrome to blunt adrenergic triggering of malignant ventricular
    arrhythmias.
  treatment_term:
    preferred_term: beta-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients were treated with beta-blockers
    explanation: >-
      Documents universal beta-blocker use in the modern international Timothy
      syndrome cohort.
  target_mechanisms:
  - target: Early afterdepolarizations and arrhythmogenic substrate
    treatment_effect: INHIBITS
    description: >-
      Beta-blockers blunt sympathetic adrenergic drive that triggers early
      afterdepolarizations in the prolonged Cav1.2-dependent action potential,
      reducing catecholamine-provoked arrhythmia.
  - target: Ventricular tachyarrhythmia (torsade de pointes)
    treatment_effect: INHIBITS
    description: >-
      By reducing adrenergic triggers, beta-blockers lower the frequency of
      torsade de pointes and sudden cardiac events in Timothy syndrome.
- name: Implantable Cardioverter-Defibrillator (ICD)
  description: >-
    ICD placement is commonly used in high-risk patients because severe
    ventricular arrhythmias and aborted cardiac arrest remain common despite
    pharmacotherapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: ICD implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:30067485
    reference_title: >-
      Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter
      International Study of a Rare Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 patients (76%) were also treated with an implantable defibrillator.
    explanation: >-
      High ICD utilization in the international cohort reflects the severe
      arrhythmic risk of Timothy syndrome.
  target_mechanisms:
  - target: Ventricular tachyarrhythmia (torsade de pointes)
    treatment_effect: MODULATES
    description: >-
      ICD detects and delivers defibrillation shocks to terminate malignant
      ventricular arrhythmias but does not address the upstream CACNA1C
      gain-of-function or prolonged repolarization.
discussions:
- discussion_id: gap_ts_fever_exacerbation_human_validity
  prompt: >-
    Does fever/elevated body temperature acutely exacerbate arrhythmia and
    seizure susceptibility in human CACNA1C carriers — including overtly normal
    heterozygotes — as it does in the zebrafish cacna1c model, and can this
    fever-provoked signal be used to find latent or mild CACNA1C-spectrum cases
    in electronic health records?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold
  - pathophysiology#Fever-associated increased seizure susceptibility
  rationale: >-
    The fever-exacerbation effect — arrhythmia and seizure-like behavior elicited
    by elevated temperature even in phenotypically normal heterozygotes — is
    demonstrated in a zebrafish cacna1c model, and the underlying premise (fever
    activates CaV1.2) is established biophysics. What is NOT established is
    whether the same fever-provoked decompensation occurs in human carriers and
    at what temperature/threshold. This is a genuine human-model-validity gap
    rather than an absence of evidence: model-system data exist, but their
    translation to human disease is the open question. Resolving it matters both
    clinically (fever management as a modifiable intervention) and for the
    hypothesis-based EHR case-finding query captured in this entry's definitions.
  proposed_experiments:
  - experiment_id: exp_ts_fever_ehr_case_finding
    name: EHR scan for fever-associated arrhythmia/seizure and CACNA1C enrichment
    description: >-
      In a genotype-linked EHR biobank (e.g. All of Us, eMERGE, or UK Biobank —
      the ICU-centric MIMIC lacks linked germline DNA and is confounded by sepsis,
      so it can prototype the phenotype logic but not validate it), execute the
      fever_exacerbated_cav1.2 case-finding query — new ventricular arrhythmia /
      QT-prolongation event or new seizure shortly after a documented febrile
      episode, in patients without prior such events — and test whether the
      identified cohort is enriched for rare/likely-pathogenic CACNA1C variants
      relative to matched controls. A positive result would support the
      hypothesis that fever unmasks latent CACNA1C-spectrum disease and validate
      the query as a case-finding tool.
    experiment_type:
      preferred_term: EHR cohort case-finding and genotype-enrichment analysis
    decision_criterion: >-
      Significant enrichment of rare/likely-pathogenic CACNA1C variants in the
      fever-associated arrhythmia/seizure cohort versus matched controls.
    supporting_outcome:
    - >-
      Fever acutely unmasks arrhythmia/seizure susceptibility in human CACNA1C
      carriers; the EHR query is a valid latent-case-finding tool.
    refuting_outcome:
    - >-
      No CACNA1C enrichment, indicating the zebrafish fever effect does not
      translate to a detectable human EHR signal (or the query lacks specificity).
  - experiment_id: exp_ts_fever_ipsc_nam_challenge
    name: >-
      Human iPSC/organ-on-chip and in-silico hyperthermia challenge of CACNA1C
      G406R
    description: >-
      Directly test whether the zebrafish fever effect is intrinsic to human
      CACNA1C-mutant cells, using New Approach Methodologies rather than an animal
      model. Subject patient-derived (and isogenic CRISPR-corrected control) human
      iPSC-derived cardiomyocytes and cortical/GABAergic neurons — and a cardiac
      microtissue/heart-on-chip — to a controlled hyperthermia challenge (raising
      temperature from 37 to ~40 degrees C), and pair this with an in-silico human
      ventricular action-potential model carrying a temperature-dependent CaV1.2
      formulation. Timothy syndrome already has human iPSC evidence for the
      baseline mechanism (PMID:21307850 cardiomyocytes, PMID:22120178 neurons), so
      adding a temperature arm to those same NAM platforms is the lowest-inferential
      -distance human-relevant test of the fever hypothesis and the natural way to
      close the zebrafish-to-human gap this discussion raises.
    experiment_type:
      preferred_term: iPSC/organ-on-chip and in-silico temperature-challenge assay
    model_systems:
    - name: CACNA1C G406R human iPSC-derived cardiomyocytes
      description: >-
        Patient-derived and isogenic CRISPR-corrected iPSC-cardiomyocytes; assess
        temperature-dependent action-potential and calcium-handling changes.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_source: patient-derived and isogenic CRISPR-corrected iPSC
    - name: CACNA1C G406R human iPSC-derived cortical/GABAergic neuronal network
      description: >-
        iPSC-derived neuronal networks on multi-electrode arrays to test
        temperature-dependent hyperexcitability and seizure-like bursting.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_source: patient-derived and isogenic CRISPR-corrected iPSC
    - name: Cardiac microtissue / heart-on-chip
      description: >-
        3D engineered human cardiac microtissue to test temperature-dependent
        arrhythmic behavior in a tissue-level NAM.
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
    - name: In-silico human ventricular action-potential model
      description: >-
        Computational human ventricular AP model with a temperature-dependent
        CaV1.2 formulation to predict fever-induced action-potential prolongation
        and early afterdepolarizations.
      experimental_model_type: OTHER
    perturbations:
    - name: Controlled hyperthermia (fever) challenge
      target: pathophysiology#Fever-triggered CaV1.2 activation and lowered arrhythmia/seizure threshold
      description: >-
        Raise culture/model temperature from 37 to ~40 degrees C, comparing mutant
        with isogenic-corrected controls.
    readouts:
    - name: Temperature-dependent APD prolongation and early afterdepolarizations
      target: pathophysiology#Ventricular tachyarrhythmia (torsade de pointes)
      description: >-
        Action-potential duration, persistent L-type calcium current, and EAD
        frequency in cardiomyocytes / microtissue at febrile versus normothermic
        temperature.
    - name: Temperature-dependent network hyperexcitability
      target: pathophysiology#Fever-associated increased seizure susceptibility
      description: >-
        Multi-electrode-array burst rate and network synchrony in iPSC-neurons at
        febrile versus normothermic temperature.
    decision_criterion: >-
      A temperature-dependent increase in APD/EAD (cardiomyocytes/microtissue) and
      network hyperexcitability (neurons) in CACNA1C G406R models but not in
      isogenic-corrected controls, reproduced in silico.
    supporting_outcome:
    - >-
      The fever effect is intrinsic to human CACNA1C-mutant cells, translating the
      zebrafish finding to human biology and raising the hypothesis from
      MODEL_SYSTEM_EXTRAPOLATION toward a human-validated mechanism.
    refuting_outcome:
    - >-
      No temperature dependence in human iPSC/organ-on-chip or in-silico models,
      indicating the zebrafish fever effect may be species-specific and not
      human-relevant.
notes: >-
  This entry addresses the listed Gene2Phenotype disease framing for
  CACNA1C-related Timothy syndrome (G2P03309, MONDO:0010979) and does not
  create a separate broader CACNA1C-related disorder entry in this PR. Recent
  international consensus reasserts classical Timothy syndrome while defining a
  broader CACNA1C-related disorder for incompletely syndromic or boundary
  phenotypes; those broader phenotypes can be split later if the knowledge base
  adds a dedicated CACNA1C spectrum entry. Classical Timothy syndrome remains
  the strongest current disease anchor for the CACNA1C gain-of-function syndrome
  with marked QT prolongation plus syndromic developmental features.

Timothy Syndrome

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