Timothy Syndrome

Mendelian MONDO:0010979 Pathograph 9 Cardiac Arrhythmia Channelopathy Neurodevelopmental Disorder

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.

Ask OpenScientist

Ask a research question about Timothy Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Definitions
1
Inheritance
8
Pathophys.
7
Phenotypes
9
Pathograph
1
Genes
2
Treatments
📘

Definitions

2
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.
👪

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.
⚙

Pathophysiology

8
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 link
voltage-gated calcium channel activity link ↑ 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 link
membrane repolarization during cardiac muscle cell action potential link ↕ DYSREGULATED cardiac muscle contraction link ↕ DYSREGULATED
heart link
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 link
cardiac muscle cell action potential link ⚠ ABNORMAL cardiac conduction link ↕ DYSREGULATED
heart link
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 link
cardiac conduction link ⚠ ABNORMAL
heart link
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 link
regulation of neuron differentiation link ↕ DYSREGULATED
brain link
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 link
neurotransmitter secretion link ↑ INCREASED
brain link
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.
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.
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.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Timothy Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Cardiovascular 3
Prolonged QT Interval 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 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 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 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 2
Autistic Behavior 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 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.
🧬

Genetic Associations

1
CACNA1C (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_a1fc2dfc-d200-40d0-9cd6-421276578e6e-2023-04-14T020000.000Z SUPPORT Other
"CACNA1C | HGNC:1390 | Timothy syndrome | MONDO:0010979 | AD | Definitive"
ClinGen classifies the CACNA1C-Timothy syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Treatments

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.
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 MAXO:0000004
ICD placement is commonly used in high-risk patients because severe ventricular arrhythmias and aborted cardiac arrest remain common despite pharmacotherapy.
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"
updated_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.
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.
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.
- 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.
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.
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.
- 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.
  treatment_term:
    preferred_term: ICD implantation
    term:
      id: MAXO:0000004
      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.
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.