DEPDC5-Related Epilepsy

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Inheritance

1

Autosomal dominant with incomplete penetrance HP:0000006

DEPDC5-related epilepsy is inherited as an autosomal dominant trait through a heterozygous germline loss-of-function allele, but penetrance is markedly incomplete: variants are frequently transmitted from clinically unaffected parents. The germline defect provides the "first hit"; a focal brain-somatic "second hit" is required for the focal cortical dysplasia lesion in a subset of carriers, which helps explain the variable expressivity.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:30093711 SUPPORT Human Clinical

"Variants were dominantly inherited from an asymptomatic parent in 64% (29/45) of the probands, illustrating the reduced penetrance of GATOR1 variants."

Quantifies the incomplete penetrance of the autosomal dominant germline allele across a large GATOR1/DEPDC5 cohort.

CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z SUPPORT Other

ClinGen classifies the DEPDC5-focal epilepsy relationship as Definitive with autosomal dominant inheritance.

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Discussions and Knowledge Gaps

3

Why do only some heterozygous DEPDC5 germline loss-of-function carriers develop epilepsy, given that up to 64% of pathogenic variants are inherited from clinically unaffected parents? What genetic, somatic, or environmental modifiers determine penetrance?

KNOWLEDGE GAP OPEN gap_depdc5_incomplete_penetrance

Attached to

pathophysiology#DEPDC5 Germline Loss of Function and GATOR1 Complex Dysfunction

The germline DEPDC5 allele is necessary but frequently insufficient for disease: a large cohort found dominant inheritance from an asymptomatic parent in 64% of probands, illustrating markedly reduced penetrance. The determinants of who among carriers becomes affected (a focal somatic second hit, additional modifier variants, or environmental triggers) are not established, and this directly limits genetic counseling.

Proposed experiments

Deep-sequencing screen for brain-somatic second hits across affected vs unaffected carriers

genetic modifier and somatic-variant association study

exp_depdc5_penetrance_somatic_screen

In carriers with epilepsy versus unaffected relatives carrying the same germline DEPDC5 variant, use high-depth sequencing of resected/biopsy brain tissue (or surrogate tissues) to test whether a focal brain-somatic second hit, additional modifier variants, or mTORC1-pathway polygenic background distinguishes affected from unaffected carriers.

Model systems

Carrier cohort with paired germline and brain-tissue sequencing

Families segregating a DEPDC5 germline variant with both affected and unaffected carriers, with access to resected epileptogenic tissue where available.

OTHER

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"Variants were dominantly inherited from an asymptomatic parent in 64% (29/45) of the probands, illustrating the reduced penetrance of GATOR1 variants."

Quantifies the incomplete penetrance that this knowledge gap seeks to explain.

Does the germline-plus-brain-somatic two-hit model account for all DEPDC5 focal cortical dysplasia (and nonlesional focal epilepsy), or do some lesions arise from germline haploinsufficiency alone or other second-hit routes?

KNOWLEDGE GAP OPEN gap_depdc5_two_hit_universality

Attached to

pathophysiology#Brain-Somatic Second-Hit Biallelic DEPDC5 Loss pathophysiology#Dysmorphic Neurons and Focal Cortical Dysplasia

The two-hit model is proven as a proof of concept in resected human tissue, with a mosaic gradient peaking at the seizure-onset zone, but somatic second hits are not detected in every DEPDC5 FCD case and nonlesional carriers have seizures without visible dysplasia. Whether biallelic loss is universally required for the lesion, or whether haploinsufficiency alone (or an undetected/undetectable somatic event) suffices, remains unresolved.

Proposed experiments

Systematic somatic second-hit detection across DEPDC5 FCD and nonlesional cortex

somatic variant prevalence study

exp_depdc5_two_hit_prevalence

Apply ultra-deep and single-nucleus sequencing to a large series of resected DEPDC5 epileptogenic specimens (both FCD-positive and MRI-normal) to quantify the fraction harboring a detectable brain-somatic second hit and correlate mutant allele fraction with histopathology severity.

Model systems

DEPDC5 surgical tissue biobank

Resected epileptogenic cortex from germline DEPDC5 carriers spanning FCD and nonlesional phenotypes.

OTHER

Show evidence (1 reference)

PMID:29708508 SUPPORT Human Clinical

"a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD"

Establishes the two-hit model as proof of concept while leaving its universality across DEPDC5 cases open.

Does mTORC1 inhibition (sirolimus/everolimus) modify seizures or epileptogenesis in humans with DEPDC5-related epilepsy, as it does in Depdc5-loss mouse models, or is the preclinical rescue not translatable?

HUMAN MODEL MISMATCH OPEN hmm_depdc5_mtor_inhibitor_human_efficacy

Attached to

pathophysiology#Constitutive mTORC1 Hyperactivation

Chronic mTORC1 inhibition rescues behavioral and biochemical deficits in neuronal Depdc5-knockout mice, providing strong model-organism support for a precision-therapy rationale. However, controlled human evidence that mTOR inhibitors reduce seizures or SUDEP risk in DEPDC5 carriers is lacking, and focal biallelic-loss lesions may respond differently from a global germline knockout; translational validity is therefore the open question.

Proposed experiments

Controlled trial of mTOR inhibition in DEPDC5/GATOR1 drug-resistant focal epilepsy

interventional clinical trial

exp_depdc5_mtor_inhibitor_trial

Conduct a controlled clinical trial (or well-powered n-of-1 series) of sirolimus or everolimus in genetically confirmed DEPDC5 drug-resistant focal epilepsy, with seizure frequency, EEG, and pharmacodynamic mTORC1 (pS6) readouts as endpoints, to test whether the mouse rescue translates to humans.

Model systems

DEPDC5 drug-resistant focal epilepsy cohort

Genetically confirmed DEPDC5 carriers with drug-resistant focal epilepsy who are not immediate surgical candidates.

OTHER

Show evidence (1 reference)

PMID:31174205 SUPPORT Model Organism

"Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans"

Model-organism evidence for mTOR-inhibitor rescue whose human translational validity is the mismatch to be resolved.

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Pathophysiology

6

DEPDC5 Germline Loss of Function and GATOR1 Complex Dysfunction

A heterozygous germline loss-of-function variant in DEPDC5 (predominantly nonsense, frameshift, or splice variants acting through haploinsufficiency) depletes functional DEPDC5, a subunit of the GATOR1 complex. GATOR1 is the amino-acid-sensing GTPase-activating repressor of mTORC1, so reduced DEPDC5 dose impairs GATOR1's ability to restrain mTORC1. This is the inherited "first hit" of the DEPDC5 mTORopathy.

neuron CL:0000540

negative regulation of TOR signaling GO:0032007 ↓ DECREASED

cerebral cortex UBERON:0000956

Downstream

Brain-Somatic Second-Hit Biallelic DEPDC5 Loss The germline haploinsufficient allele sets the stage for a focal somatic second hit that completes biallelic DEPDC5 inactivation in a neuronal clone.

Constitutive mTORC1 Hyperactivation Even at the germline haploinsufficient baseline, weakened GATOR1 restraint biases mTORC1 toward hyperactivation.

Show evidence (3 references)

PMID:29708508 SUPPORT Human Clinical

"DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway"

Establishes DEPDC5 as the GATOR1 repressor of the amino-acid-sensing branch of mTORC1, the protein whose germline loss triggers the disorder.

PMID:30093711 SUPPORT Human Clinical

"haploinsufficiency has been shown to be the pathogenic mechanism"

Confirms haploinsufficiency of the GATOR1 subunit as the pathogenic mechanism of the germline first hit.

PMID:23542697 SUPPORT Human Clinical

"This high frequency establishes DEPDC5 mutations as a common cause of familial focal"

Establishes DEPDC5 loss-of-function variants as a common cause of familial focal epilepsy.

Brain-Somatic Second-Hit Biallelic DEPDC5 Loss

In the subset of DEPDC5 carriers who develop a focal cortical lesion, a post-zygotic brain-somatic DEPDC5 variant arising during cortical development inactivates the second allele in trans within a focal neuronal clone. Deep sequencing of resected human epileptogenic cortex reveals a mosaic gradient, with the highest mutant fraction in the seizure-onset zone, providing proof of concept for a biallelic germline-plus-somatic two-hit mechanism that explains the focal nature of the dysplasia.

neuron CL:0000540

negative regulation of TOR signaling GO:0032007 ↓ DECREASED

cerebral cortex UBERON:0000956

Downstream

Constitutive mTORC1 Hyperactivation Biallelic DEPDC5 loss abolishes GATOR1 restraint focally, driving constitutive mTORC1 hyperactivation in the mutant clone.

Show evidence (2 references)

PMID:29708508 SUPPORT Human Clinical

"a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD"

Directly establishes the germline-plus-brain-somatic two-hit model in human DEPDC5 focal epilepsy with FCD.

PMID:29708508 SUPPORT Human Clinical

"We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone"

Shows the focal somatic mosaic gradient concentrated at the seizure-onset zone, supporting a focal second hit.

Constitutive mTORC1 Hyperactivation

Loss of GATOR1 inhibition releases mTORC1 into constitutive, amino-acid-independent hyperactivation. In human resected DEPDC5 cortex this is detected as increased phosphorylation of ribosomal protein S6, a canonical readout of mTORC1 activity. mTORC1 hyperactivation is the shared central effector of the focal DEPDC5 mTORopathy.

neuron CL:0000540

positive regulation of TOR signaling GO:0032008 ↑ INCREASED TOR signaling GO:0031929 ↑ INCREASED

cerebral cortex UBERON:0000956

Downstream

Dysmorphic Neurons and Focal Cortical Dysplasia Sustained neuronal mTORC1 hyperactivation drives cytomegaly, abnormal dendritic/spine morphology, and focal cortical dysplasia.

Show evidence (2 references)

PMID:30093711 SUPPORT Human Clinical

"The pathogenic molecular mechanism linked to GATOR1 haploinsufficiency is a hyperactivation of mTORC1 pathway"

Identifies mTORC1 hyperactivation as the pathogenic molecular consequence of GATOR1/DEPDC5 loss.

PMID:29708508 SUPPORT Human Clinical

"we detected increased phosphorylation levels of the ribosomal protein S6, a well-known readout of mTORC1 activity"

Demonstrates increased mTORC1 activity (pS6) in DEPDC5-mutant human cortical neurons.

Dysmorphic Neurons and Focal Cortical Dysplasia

Neuronal mTORC1 hyperactivation produces enlarged (cytomegalic/dysmorphic) neurons with altered dendrite and spine morphology and disturbs cortical lamination, yielding focal cortical dysplasia (predominantly FCD type II). This is the structural lesion of the two-hit arm of DEPDC5 epilepsy.

pyramidal neuron CL:0000598

TOR signaling GO:0031929 ↑ INCREASED

cerebral cortex UBERON:0000956

Downstream

Focal Cortical Hyperexcitability and Focal-Onset Seizures Dysplastic, mTORC1-hyperactive cortex forms an epileptogenic focus that generates focal-onset seizures; nonlesional carriers can also be hyperexcitable without visible dysplasia.

Show evidence (2 references)

PMID:29708508 SUPPORT Model Organism

"We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons"

Links Depdc5 loss to abnormal dendrite and spine morphology of excitatory neurons, the cellular basis of the dysplastic lesion.

PMID:30093711 SUPPORT Human Clinical

"The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%)"

Documents focal cortical dysplasia in about 20% of the GATOR1/DEPDC5 cohort.

Focal Cortical Hyperexcitability and Focal-Onset Seizures

The mTORC1-hyperactive focus (dysplastic in lesional cases, or structurally normal in nonlesional carriers) becomes hyperexcitable and hypersynchronous, generating recurrent focal-onset seizures. Across DEPDC5 carriers the seizure focus varies (frontal, temporal, and other cortical regions) and seizures are frequently sleep-related and drug-resistant.

pyramidal neuron CL:0000598

TOR signaling GO:0031929 ↑ INCREASED

cerebral cortex UBERON:0000956

Downstream

Elevated Risk of Sudden Unexpected Death in Epilepsy Recurrent, frequently sleep-related and drug-resistant focal seizures in DEPDC5 carriers are associated with a disproportionately high SUDEP risk; whether GATOR1 loss also acts directly on cardiorespiratory control is unresolved.

Show evidence (2 references)

PMID:23542697 SUPPORT Human Clinical

"Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction"

Localizes DEPDC5 to human neurons and implicates it in neuronal signal transduction underlying the epileptogenic focus.

PMID:30093711 SUPPORT Human Clinical

"The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%)"

Characterizes the DEPDC5/GATOR1 focal, sleep-related, drug-resistant seizure phenotype.

Elevated Risk of Sudden Unexpected Death in Epilepsy

DEPDC5-related epilepsy carries a notably elevated risk of sudden unexpected death in epilepsy (SUDEP), reported in roughly 10% of GATOR1 families and documented as definite SUDEP within DEPDC5 pedigrees. The recognized SUDEP risk factors present in this disorder (early onset, drug resistance, and sleep-related seizures) contribute, but a gene-intrinsic effect (possibly via cardiorespiratory control) is hypothesized and remains an open question.

neuron CL:0000540

brain UBERON:0000955

Show evidence (2 references)

PMID:30093711 SUPPORT Human Clinical

"Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families"

Quantifies the elevated SUDEP rate across GATOR1/DEPDC5 families.

PMID:27066565 SUPPORT Human Clinical

"We report a family with epilepsy due to DEPDC5 mutation and 2 definite cases of SUDEP within this family"

Documents definite SUDEP cases segregating in a DEPDC5 family.

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Pathograph

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Phenotypes

6

Nervous System 2

Focal-Onset Seizures With Variable Foci HP:0007359

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%)"

Establishes focal-onset seizures as the predominant DEPDC5/GATOR1 phenotype.

Variable Cognition (Normal to Impaired) OCCASIONAL Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"Cognitive impairment and/or psychiatric comorbidities were reported in 60% of the probands of this cohort"

Documents variable cognitive/psychiatric involvement, more frequent in early-onset cases, consistent with variable-to-normal cognition overall.

Constitutional 1

Elevated SUDEP Risk Sudden unexpected death in epilepsy HP:0033258

Show evidence (2 references)

PMID:30093711 SUPPORT Human Clinical

"Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families"

Quantifies the elevated SUDEP frequency in the DEPDC5/GATOR1 cohort.

PMID:27066565 SUPPORT Human Clinical

"We report a family with epilepsy due to DEPDC5 mutation and 2 definite cases of SUDEP within this family"

Reports definite SUDEP cases within a DEPDC5 family.

Other 3

Focal Cortical Dysplasia HP:0032046

Show evidence (2 references)

PMID:29708508 SUPPORT Human Clinical

"a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD"

Links the two-hit DEPDC5 mechanism to focal cortical dysplasia.

PMID:30093711 SUPPORT Human Clinical

"The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%)"

Quantifies focal cortical dysplasia in the DEPDC5/GATOR1 cohort.

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Genetic Associations

1

DEPDC5 (Causal GATOR1 loss-of-function variant (haploinsufficiency))

Gene: DEPDC5 hgnc:18423

Show evidence (2 references)

PMID:23542697 SUPPORT Human Clinical

"This high frequency establishes DEPDC5 mutations as a common cause of familial focal"

Establishes DEPDC5 as a common causal gene in familial focal epilepsy.

CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z SUPPORT Other

ClinGen rates the DEPDC5-focal epilepsy relationship as Definitive.

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Medical Actions

3

Antiseizure Medication Therapy

Action: anticonvulsant agent therapy Ontology label: Anticonvulsant Therapy NCIT:C64172

First-line management uses antiseizure medications for focal epilepsy. Response is variable and drug resistance is common (about half of carriers, higher in sleep-related/FCD cases).

Target Phenotypes: Focal-onset seizure HP:0007359

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%)"

Establishes focal epilepsy treated with antiseizure medications and its frequent drug resistance.

mTOR Inhibitor Precision Therapy (Sirolimus/Everolimus)

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168 everolimus CHEBI:68478

Because DEPDC5 epilepsy is a focal mTORopathy, mTORC1 inhibitors (rapamycin/ sirolimus, everolimus) are a mechanism-directed precision-therapy strategy. Preclinical evidence shows chronic mTORC1 inhibition rescues deficits from neuronal Depdc5 loss; human use remains investigational rather than established care.

Mechanism Target:

INHIBITS Constitutive mTORC1 Hyperactivation — mTOR inhibitors directly counteract the constitutive mTORC1 hyperactivation that results from loss of GATOR1 restraint.

Show evidence (1 reference)

PMID:31174205 SUPPORT Model Organism

"Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans"

Depdc5 knockout mouse data support mTORC1 inhibition as a mechanistically rational therapy targeting the hyperactivated pathway.

Target Phenotypes: Focal-onset seizure HP:0007359

Show evidence (2 references)

PMID:29708508 SUPPORT Model Organism

"This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules"

Supports mTORC1-targeting molecules as a therapeutic avenue for DEPDC5 focal epilepsy.

PMID:30093711 SUPPORT Human Clinical

"Currently available mTORC1 inhibitors, such as rapamycin, represent promising drugs in the treatment of focal epilepsies"

Frames mTORC1 inhibitors as promising drugs for GATOR1/DEPDC5 focal epilepsies.

Epilepsy Surgery for Drug-Resistant Focal Cortical Dysplasia

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Focal resection of the epileptogenic dysplastic cortex can achieve seizure freedom in drug-resistant DEPDC5-associated FCD, including cases with subtle MRI; a germline GATOR1 variant is not a contraindication to surgery.

Mechanism Target:

MODULATES Dysmorphic Neurons and Focal Cortical Dysplasia — Focal resection removes the epileptogenic dysplastic cortex when localizable.

Show evidence (1 reference)

PMID:29708508 SUPPORT Human Clinical

"We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone"

The somatic mutation gradient concentrated at the seizure-onset zone supports focal resection targeting.

Target Phenotypes: Focal cortical dysplasia HP:0032046 Focal-onset seizure HP:0007359

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Diagnosis

1

DEPDC5 molecular genetic testing

Epilepsy gene panels or exome/genome sequencing identify a heterozygous germline pathogenic DEPDC5 variant. When a resected epileptogenic lesion is available, deep (high-depth) sequencing of brain tissue can detect a brain-somatic second-hit variant not present in blood.

molecular genetic testing NCIT:C19770

Results: A heterozygous pathogenic/likely pathogenic DEPDC5 loss-of-function variant supports the diagnosis; a brain-somatic DEPDC5 variant in resected tissue supports the two-hit FCD mechanism.

Show evidence (1 reference)

PMID:29708508 SUPPORT Human Clinical

"We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone"

Supports deep sequencing of resected epileptogenic cortex to detect the brain-somatic second hit.

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Prevalence

1

Worldwide (genetic focal epilepsy, DEPDC5 contribution)

Point Prevalence 30.0 per 100,000 Rare

Derived estimate. Baldassari et al. estimated a population prevalence of genetic focal epilepsies of 0.32%, with DEPDC5 contributing ~9.4% of genetic focal epilepsy (0.32% x 9.4% ~= 0.03% ~= 30 per 100,000). The figure is penetrance-dependent and approximate; DEPDC5 is nonetheless the most common single-gene cause of GATOR1/familial focal epilepsies.

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"We estimated the prevalence of genetic focal epilepsies in the population to be 0.32%, a contribution of DEPDC5 gene to genetic focal epilepsy of 9.4%"

Provides the two figures from which the DEPDC5 focal-epilepsy population estimate is derived.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from DEPDC5-Related Epilepsy:

Familial Focal Epilepsy With Variable Foci

Overlapping Features FFEVF is one clinical presentation within the DEPDC5/GATOR1 spectrum and can be caused by DEPDC5, NPRL2, or NPRL3. This gene-anchored entry is scoped to the DEPDC5-to-mTORC1 mechanism and its two-hit lesion biology across the whole DEPDC5 spectrum; the FFEVF familial syndrome as such is curated separately.

Show evidence (1 reference)

PMID:27066565 SUPPORT Human Clinical

"DEPDC5 has been associated with a variety of familial epilepsies, including familial focal epilepsy with variable foci, autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, epileptic spasms, and cortical dysplasia"

Places FFEVF as one of several DEPDC5-associated familial epilepsy presentations, distinguishing the gene-anchored spectrum.

Tuberous Sclerosis Complex and other mTORopathies

Overlapping Features TSC (TSC1/TSC2) and MTOR/AKT3/PIK3CA-related focal cortical dysplasia/ hemimegalencephaly share mTORC1 hyperactivation but differ in gene, systemic features, and lesion distribution; DEPDC5 acts upstream through GATOR1.

Show evidence (1 reference)

PMID:30093711 SUPPORT Human Clinical

"The pathogenic molecular mechanism linked to GATOR1 haploinsufficiency is a hyperactivation of mTORC1 pathway"

Situates DEPDC5 within the mTORopathies, whose shared effector is mTORC1 hyperactivation.

{ }

Source YAML

click to show

name: DEPDC5-Related Epilepsy
creation_date: "2026-07-25T00:00:00Z"
category: Mendelian
description: >-
  DEPDC5-related epilepsy is the gene-anchored spectrum of focal epilepsies caused
  by loss-of-function variants in DEPDC5, which encodes a subunit of the GATOR1
  complex (with NPRL2 and NPRL3) that inhibits the amino-acid-sensing branch of
  mTORC1. Loss of GATOR1 restraint releases mTORC1 into constitutive
  hyperactivation, defining a focal "mTORopathy." Mechanistically the disorder is
  distinguished by a germline-plus-brain-somatic two-hit model: a heterozygous
  germline loss-of-function allele is inherited with incomplete penetrance, and a
  focal brain-somatic second hit produces biallelic DEPDC5 loss in a neuronal
  clone, driving focal cortical dysplasia. Clinically it spans familial focal
  epilepsy with variable foci, sleep-related (frontal-lobe/hypermotor) focal
  epilepsy, familial mesial temporal lobe epilepsy, focal epilepsy with focal
  cortical dysplasia, and severe early-onset developmental and epileptic
  encephalopathy, and it carries a notably elevated risk of sudden unexpected
  death in epilepsy (SUDEP). This entry is scoped to the DEPDC5/GATOR1-to-mTORC1
  mechanism, the two-hit lesion model, and the resulting precision-therapy
  rationale (mTOR inhibitors); the familial variable-foci clinical syndrome as
  such is curated separately in Familial Focal Epilepsy With Variable Foci.
disease_term:
  preferred_term: DEPDC5-related focal epilepsy
  term:
    id: MONDO:0005384
    label: focal epilepsy
synonyms:
- DEPDC5-related focal epilepsy
- GATOR1-related epilepsy
- DEPDC5 encephalopathy
- focal epilepsy, DEPDC5-related
parents:
- Epilepsy
inheritance:
- name: Autosomal dominant with incomplete penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    DEPDC5-related epilepsy is inherited as an autosomal dominant trait through a
    heterozygous germline loss-of-function allele, but penetrance is markedly
    incomplete: variants are frequently transmitted from clinically unaffected
    parents. The germline defect provides the "first hit"; a focal brain-somatic
    "second hit" is required for the focal cortical dysplasia lesion in a subset
    of carriers, which helps explain the variable expressivity.
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were dominantly inherited from an asymptomatic parent in 64%
      (29/45) of the probands, illustrating the reduced penetrance of GATOR1
      variants.
    explanation: >-
      Quantifies the incomplete penetrance of the autosomal dominant germline
      allele across a large GATOR1/DEPDC5 cohort.
  - reference: CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z
    reference_title: "DEPDC5 / focal epilepsy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DEPDC5 | HGNC:18423 | focal epilepsy | MONDO:0005384 | AD | Definitive | SOP9 | Epilepsy Gene Curation Expert Panel | 2018-08-07T04:00:00.000Z"
    explanation: >-
      ClinGen classifies the DEPDC5-focal epilepsy relationship as Definitive with
      autosomal dominant inheritance.
prevalence:
- population: Worldwide (genetic focal epilepsy, DEPDC5 contribution)
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  rate_per_100000: 30.0
  notes: >-
    Derived estimate. Baldassari et al. estimated a population prevalence of
    genetic focal epilepsies of 0.32%, with DEPDC5 contributing ~9.4% of genetic
    focal epilepsy (0.32% x 9.4% ~= 0.03% ~= 30 per 100,000). The figure is
    penetrance-dependent and approximate; DEPDC5 is nonetheless the most common
    single-gene cause of GATOR1/familial focal epilepsies.
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We estimated the prevalence of genetic focal epilepsies in the population
      to be 0.32%, a contribution of DEPDC5 gene to genetic focal epilepsy of
      9.4%
    explanation: >-
      Provides the two figures from which the DEPDC5 focal-epilepsy population
      estimate is derived.
references:
- reference: PMID:23542697
  title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
- reference: PMID:29708508
  title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
- reference: PMID:30093711
  title: The landscape of epilepsy-related GATOR1 variants.
- reference: PMID:27066565
  title: Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.
- reference: PMID:31174205
  title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
- reference: CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z
  title: DEPDC5 / focal epilepsy (Definitive)
pathophysiology:
- name: DEPDC5 Germline Loss of Function and GATOR1 Complex Dysfunction
  description: >-
    A heterozygous germline loss-of-function variant in DEPDC5 (predominantly
    nonsense, frameshift, or splice variants acting through haploinsufficiency)
    depletes functional DEPDC5, a subunit of the GATOR1 complex. GATOR1 is the
    amino-acid-sensing GTPase-activating repressor of mTORC1, so reduced DEPDC5
    dose impairs GATOR1's ability to restrain mTORC1. This is the inherited
    "first hit" of the DEPDC5 mTORopathy.
  role: trigger
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: negative regulation of TOR signaling
    modifier: DECREASED
    term:
      id: GO:0032007
      label: negative regulation of TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently
      recognized amino acid-sensing branch of the mTORC1 pathway
    explanation: >-
      Establishes DEPDC5 as the GATOR1 repressor of the amino-acid-sensing branch
      of mTORC1, the protein whose germline loss triggers the disorder.
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      haploinsufficiency has been shown to be the pathogenic mechanism
    explanation: >-
      Confirms haploinsufficiency of the GATOR1 subunit as the pathogenic
      mechanism of the germline first hit.
  - reference: PMID:23542697
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This high frequency establishes DEPDC5 mutations as a common cause of
      familial focal
    explanation: >-
      Establishes DEPDC5 loss-of-function variants as a common cause of familial
      focal epilepsy.
  downstream:
  - target: Brain-Somatic Second-Hit Biallelic DEPDC5 Loss
    causal_link_type: DIRECT
    description: >-
      The germline haploinsufficient allele sets the stage for a focal somatic
      second hit that completes biallelic DEPDC5 inactivation in a neuronal clone.
  - target: Constitutive mTORC1 Hyperactivation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced GATOR1 GTPase-activating restraint of the Rag GTPases
    description: >-
      Even at the germline haploinsufficient baseline, weakened GATOR1 restraint
      biases mTORC1 toward hyperactivation.
- name: Brain-Somatic Second-Hit Biallelic DEPDC5 Loss
  description: >-
    In the subset of DEPDC5 carriers who develop a focal cortical lesion, a
    post-zygotic brain-somatic DEPDC5 variant arising during cortical development
    inactivates the second allele in trans within a focal neuronal clone. Deep
    sequencing of resected human epileptogenic cortex reveals a mosaic gradient,
    with the highest mutant fraction in the seizure-onset zone, providing proof of
    concept for a biallelic germline-plus-somatic two-hit mechanism that explains
    the focal nature of the dysplasia.
  role: driver
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: negative regulation of TOR signaling
    modifier: DECREASED
    term:
      id: GO:0032007
      label: negative regulation of TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a biallelic 2-hit - brain somatic and germline - mutational mechanism in
      DEPDC5 causes focal epilepsy with FCD
    explanation: >-
      Directly establishes the germline-plus-brain-somatic two-hit model in human
      DEPDC5 focal epilepsy with FCD.
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered a mutation gradient with a higher rate of mosaicism in the
      seizure-onset zone than in the surrounding epileptogenic zone
    explanation: >-
      Shows the focal somatic mosaic gradient concentrated at the seizure-onset
      zone, supporting a focal second hit.
  downstream:
  - target: Constitutive mTORC1 Hyperactivation
    causal_link_type: DIRECT
    description: >-
      Biallelic DEPDC5 loss abolishes GATOR1 restraint focally, driving
      constitutive mTORC1 hyperactivation in the mutant clone.
- name: Constitutive mTORC1 Hyperactivation
  description: >-
    Loss of GATOR1 inhibition releases mTORC1 into constitutive,
    amino-acid-independent hyperactivation. In human resected DEPDC5 cortex this is detected
    as increased phosphorylation of ribosomal protein S6, a canonical readout of
    mTORC1 activity. mTORC1 hyperactivation is the shared central effector of the
    focal DEPDC5 mTORopathy.
  role: central_effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: positive regulation of TOR signaling
    modifier: INCREASED
    term:
      id: GO:0032008
      label: positive regulation of TOR signaling
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenic molecular mechanism linked to GATOR1 haploinsufficiency is a
      hyperactivation of mTORC1 pathway
    explanation: >-
      Identifies mTORC1 hyperactivation as the pathogenic molecular consequence of
      GATOR1/DEPDC5 loss.
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we detected increased phosphorylation levels of the ribosomal protein S6, a
      well-known readout of mTORC1 activity
    explanation: >-
      Demonstrates increased mTORC1 activity (pS6) in DEPDC5-mutant human cortical
      neurons.
  downstream:
  - target: Dysmorphic Neurons and Focal Cortical Dysplasia
    causal_link_type: DIRECT
    description: >-
      Sustained neuronal mTORC1 hyperactivation drives cytomegaly, abnormal
      dendritic/spine morphology, and focal cortical dysplasia.
- name: Dysmorphic Neurons and Focal Cortical Dysplasia
  description: >-
    Neuronal mTORC1 hyperactivation produces enlarged (cytomegalic/dysmorphic)
    neurons with altered dendrite and spine morphology and disturbs cortical
    lamination, yielding focal cortical dysplasia (predominantly FCD type II).
    This is the structural lesion of the two-hit arm of DEPDC5 epilepsy.
  role: effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We further unveil a key role of Depdc5 in shaping dendrite and spine
      morphology of excitatory neurons
    explanation: >-
      Links Depdc5 loss to abnormal dendrite and spine morphology of excitatory
      neurons, the cellular basis of the dysplastic lesion.
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Documents focal cortical dysplasia in about 20% of the GATOR1/DEPDC5 cohort.
  downstream:
  - target: Focal Cortical Hyperexcitability and Focal-Onset Seizures
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical microcircuit excitation-inhibition balance
    description: >-
      Dysplastic, mTORC1-hyperactive cortex forms an epileptogenic focus that
      generates focal-onset seizures; nonlesional carriers can also be
      hyperexcitable without visible dysplasia.
- name: Focal Cortical Hyperexcitability and Focal-Onset Seizures
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    The mTORC1-hyperactive focus (dysplastic in lesional cases, or
    structurally normal in nonlesional carriers) becomes hyperexcitable and
    hypersynchronous, generating recurrent focal-onset seizures. Across DEPDC5
    carriers the seizure focus varies (frontal, temporal, and other cortical
    regions) and seizures are frequently sleep-related and drug-resistant.
  role: effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:23542697
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared homology with G protein signaling molecules and localization in human
      neurons suggest a role of DEPDC5 in neuronal signal transduction
    explanation: >-
      Localizes DEPDC5 to human neurons and implicates it in neuronal signal
      transduction underlying the epileptogenic focus.
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Characterizes the DEPDC5/GATOR1 focal, sleep-related, drug-resistant seizure
      phenotype.
  downstream:
  - target: Elevated Risk of Sudden Unexpected Death in Epilepsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent, frequently sleep-related and drug-resistant focal seizures in
      DEPDC5 carriers are associated with a disproportionately high SUDEP risk;
      whether GATOR1 loss also acts directly on cardiorespiratory control is
      unresolved.
- name: Elevated Risk of Sudden Unexpected Death in Epilepsy
  description: >-
    DEPDC5-related epilepsy carries a notably elevated risk of sudden unexpected
    death in epilepsy (SUDEP), reported in roughly 10% of GATOR1 families and
    documented as definite SUDEP within DEPDC5 pedigrees. The recognized SUDEP
    risk factors present in this disorder (early onset, drug resistance, and
    sleep-related seizures) contribute, but a gene-intrinsic effect (possibly via
    cardiorespiratory control) is hypothesized and remains an open question.
  role: outcome
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families
    explanation: >-
      Quantifies the elevated SUDEP rate across GATOR1/DEPDC5 families.
  - reference: PMID:27066565
    reference_title: Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a family with epilepsy due to DEPDC5 mutation and 2 definite cases
      of SUDEP within this family
    explanation: >-
      Documents definite SUDEP cases segregating in a DEPDC5 family.
phenotypes:
- name: Focal-Onset Seizures With Variable Foci
  category: Neurological
  diagnostic: true
  description: >-
    Focal-onset seizures are the core manifestation; the seizure focus varies
    across DEPDC5 carriers (frontal, temporal, and other cortical regions),
    while each individual's focus tends to remain constant.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Establishes focal-onset seizures as the predominant DEPDC5/GATOR1 phenotype.
- name: Sleep-Related Hypermotor (Frontal-Lobe) Seizures
  category: Neurological
  description: >-
    A large proportion of DEPDC5 carriers have sleep-related hypermotor
    (hyperkinetic) focal seizures, historically termed autosomal dominant
    nocturnal frontal lobe epilepsy / sleep-related hypermotor epilepsy.
  phenotype_term:
    preferred_term: Sleep-related hypermotor seizure
    term:
      id: HP:0011174
      label: Focal hyperkinetic seizure
    temporality: NOCTURNAL
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Documents sleep-related hypermotor/frontal-lobe seizures in about half the
      cohort.
- name: Nocturnal (Sleep-Related) Seizures
  category: Neurological
  description: >-
    Seizures in DEPDC5-related epilepsy occur predominantly during sleep in a
    large fraction of carriers, a feature that also contributes to SUDEP risk.
  phenotype_term:
    preferred_term: Nocturnal seizures
    term:
      id: HP:0031951
      label: Nocturnal seizures
    temporality: NOCTURNAL
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      often sleep-related and drug-resistant (54%)
    explanation: >-
      Supports the predominantly sleep-related occurrence of DEPDC5/GATOR1
      seizures.
- name: Focal Cortical Dysplasia
  category: Neurological
  description: >-
    A subset of DEPDC5 carriers, particularly those with a brain-somatic second
    hit, have focal cortical dysplasia (predominantly FCD type II), which
    underlies drug-resistant focal epilepsy amenable to surgery.
  phenotype_term:
    preferred_term: Focal cortical dysplasia
    term:
      id: HP:0032046
      label: Focal cortical dysplasia
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a biallelic 2-hit - brain somatic and germline - mutational mechanism in
      DEPDC5 causes focal epilepsy with FCD
    explanation: >-
      Links the two-hit DEPDC5 mechanism to focal cortical dysplasia.
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Quantifies focal cortical dysplasia in the DEPDC5/GATOR1 cohort.
- name: Variable Cognition (Normal to Impaired)
  category: Neurological
  description: >-
    Cognition is variable in DEPDC5-related epilepsy: many carriers have normal
    intelligence, while cognitive impairment and psychiatric comorbidities are
    more common in early-onset (encephalopathic) presentations.
  phenotype_term:
    preferred_term: Cognitive impairment (variable)
    term:
      id: HP:0100543
      label: Cognitive impairment
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive impairment and/or psychiatric comorbidities were reported in 60%
      of the probands of this cohort
    explanation: >-
      Documents variable cognitive/psychiatric involvement, more frequent in
      early-onset cases, consistent with variable-to-normal cognition overall.
- name: Elevated SUDEP Risk
  category: Neurological
  description: >-
    DEPDC5-related epilepsy is associated with a disproportionately high rate of
    sudden unexpected death in epilepsy relative to focal epilepsy generally.
  phenotype_term:
    preferred_term: Sudden unexpected death in epilepsy
    term:
      id: HP:0033258
      label: Sudden unexpected death in epilepsy
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families
    explanation: >-
      Quantifies the elevated SUDEP frequency in the DEPDC5/GATOR1 cohort.
  - reference: PMID:27066565
    reference_title: Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a family with epilepsy due to DEPDC5 mutation and 2 definite cases
      of SUDEP within this family
    explanation: >-
      Reports definite SUDEP cases within a DEPDC5 family.
genetic:
- name: DEPDC5
  association: Causal GATOR1 loss-of-function variant (haploinsufficiency)
  gene_term:
    preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  notes: >-
    DEPDC5 encodes a subunit of the GATOR1 complex (with NPRL2 and NPRL3), the
    amino-acid-sensing GTPase-activating repressor of mTORC1. Germline truncating
    and splice-altering variants act by haploinsufficiency; a focal brain-somatic
    second hit can produce biallelic loss and focal cortical dysplasia. DEPDC5 is
    the most frequent GATOR1 gene in familial focal epilepsies.
  case_fractions:
  - population: Small familial focal epilepsy families (unable to be diagnosed as FFEVF clinically)
    case_fraction_percent: 12.0
    cohort_size: 82
    notes: DEPDC5 mutations in 10/82 small focal-epilepsy families.
    evidence:
    - reference: PMID:23542697
      reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This high frequency establishes DEPDC5 mutations as a common cause of
        familial focal
      explanation: DEPDC5 identified in ~12% (10/82) of small familial focal epilepsy families.
  - population: Genetic focal epilepsy (population contribution estimate)
    case_fraction_percent: 9.4
    notes: Estimated DEPDC5 contribution to genetic focal epilepsy.
    evidence:
    - reference: PMID:30093711
      reference_title: The landscape of epilepsy-related GATOR1 variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We estimated the prevalence of genetic focal epilepsies in the population
        to be 0.32%, a contribution of DEPDC5 gene to genetic focal epilepsy of
        9.4%
      explanation: Estimates DEPDC5 as ~9.4% of genetic focal epilepsy.
  evidence:
  - reference: PMID:23542697
    reference_title: Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This high frequency establishes DEPDC5 mutations as a common cause of
      familial focal
    explanation: Establishes DEPDC5 as a common causal gene in familial focal epilepsy.
  - reference: CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z
    reference_title: "DEPDC5 / focal epilepsy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DEPDC5 | HGNC:18423 | focal epilepsy | MONDO:0005384 | AD | Definitive | SOP9 | Epilepsy Gene Curation Expert Panel | 2018-08-07T04:00:00.000Z"
    explanation: ClinGen rates the DEPDC5-focal epilepsy relationship as Definitive.
diagnosis:
- name: DEPDC5 molecular genetic testing
  description: >-
    Epilepsy gene panels or exome/genome sequencing identify a heterozygous
    germline pathogenic DEPDC5 variant. When a resected epileptogenic lesion is
    available, deep (high-depth) sequencing of brain tissue can detect a
    brain-somatic second-hit variant not present in blood.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: >-
    A heterozygous pathogenic/likely pathogenic DEPDC5 loss-of-function variant
    supports the diagnosis; a brain-somatic DEPDC5 variant in resected tissue
    supports the two-hit FCD mechanism.
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered a mutation gradient with a higher rate of mosaicism in the
      seizure-onset zone than in the surrounding epileptogenic zone
    explanation: >-
      Supports deep sequencing of resected epileptogenic cortex to detect the
      brain-somatic second hit.
differential_diagnoses:
- name: Familial Focal Epilepsy With Variable Foci
  description: >-
    FFEVF is one clinical presentation within the DEPDC5/GATOR1 spectrum and can
    be caused by DEPDC5, NPRL2, or NPRL3. This gene-anchored entry is scoped to
    the DEPDC5-to-mTORC1 mechanism and its two-hit lesion biology across the whole
    DEPDC5 spectrum; the FFEVF familial syndrome as such is curated separately.
  evidence:
  - reference: PMID:27066565
    reference_title: Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DEPDC5 has been associated with a variety of familial epilepsies, including
      familial focal epilepsy with variable foci, autosomal dominant nocturnal
      frontal lobe epilepsy, familial temporal lobe epilepsy, epileptic spasms,
      and cortical dysplasia
    explanation: >-
      Places FFEVF as one of several DEPDC5-associated familial epilepsy
      presentations, distinguishing the gene-anchored spectrum.
- name: Tuberous Sclerosis Complex and other mTORopathies
  description: >-
    TSC (TSC1/TSC2) and MTOR/AKT3/PIK3CA-related focal cortical dysplasia/
    hemimegalencephaly share mTORC1 hyperactivation but differ in gene, systemic
    features, and lesion distribution; DEPDC5 acts upstream through GATOR1.
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenic molecular mechanism linked to GATOR1 haploinsufficiency is a
      hyperactivation of mTORC1 pathway
    explanation: >-
      Situates DEPDC5 within the mTORopathies, whose shared effector is mTORC1
      hyperactivation.
treatments:
- name: Antiseizure Medication Therapy
  description: >-
    First-line management uses antiseizure medications for focal epilepsy.
    Response is variable and drug resistance is common (about half of carriers,
    higher in sleep-related/FCD cases).
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g.,
      hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4
      years, often sleep-related and drug-resistant (54%), and associated with
      focal cortical dysplasia (20%)
    explanation: >-
      Establishes focal epilepsy treated with antiseizure medications and its
      frequent drug resistance.
- name: mTOR Inhibitor Precision Therapy (Sirolimus/Everolimus)
  description: >-
    Because DEPDC5 epilepsy is a focal mTORopathy, mTORC1 inhibitors (rapamycin/
    sirolimus, everolimus) are a mechanism-directed precision-therapy strategy.
    Preclinical evidence shows chronic mTORC1 inhibition rescues deficits from
    neuronal Depdc5 loss; human use remains investigational rather than
    established care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
    - preferred_term: everolimus
      term:
        id: CHEBI:68478
        label: everolimus
  target_phenotypes:
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  target_mechanisms:
  - target: Constitutive mTORC1 Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      mTOR inhibitors directly counteract the constitutive mTORC1 hyperactivation
      that results from loss of GATOR1 restraint.
    evidence:
    - reference: PMID:31174205
      reference_title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Collectively, our data provide the first evidence of behavioral
        alterations in mice with Depdc5 loss and support mTOR inhibition as a
        rational therapeutic strategy for DEPDC5-related epilepsy in humans
      explanation: >-
        Depdc5 knockout mouse data support mTORC1 inhibition as a mechanistically
        rational therapy targeting the hyperactivated pathway.
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This study reveals promising therapeutic avenues for treating drug-resistant
      focal epilepsies with mTORC1-targeting molecules
    explanation: >-
      Supports mTORC1-targeting molecules as a therapeutic avenue for DEPDC5 focal
      epilepsy.
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently available mTORC1 inhibitors, such as rapamycin, represent promising
      drugs in the treatment of focal epilepsies
    explanation: >-
      Frames mTORC1 inhibitors as promising drugs for GATOR1/DEPDC5 focal
      epilepsies.
- name: Epilepsy Surgery for Drug-Resistant Focal Cortical Dysplasia
  description: >-
    Focal resection of the epileptogenic dysplastic cortex can achieve seizure
    freedom in drug-resistant DEPDC5-associated FCD, including cases with subtle
    MRI; a germline GATOR1 variant is not a contraindication to surgery.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Focal cortical dysplasia
    term:
      id: HP:0032046
      label: Focal cortical dysplasia
  - preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  target_mechanisms:
  - target: Dysmorphic Neurons and Focal Cortical Dysplasia
    treatment_effect: MODULATES
    description: Focal resection removes the epileptogenic dysplastic cortex when localizable.
    evidence:
    - reference: PMID:29708508
      reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We discovered a mutation gradient with a higher rate of mosaicism in the
        seizure-onset zone than in the surrounding epileptogenic zone
      explanation: >-
        The somatic mutation gradient concentrated at the seizure-onset zone
        supports focal resection targeting.
discussions:
- discussion_id: gap_depdc5_incomplete_penetrance
  prompt: >-
    Why do only some heterozygous DEPDC5 germline loss-of-function carriers develop
    epilepsy, given that up to 64% of pathogenic variants are inherited from
    clinically unaffected parents? What genetic, somatic, or environmental modifiers
    determine penetrance?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#DEPDC5 Germline Loss of Function and GATOR1 Complex Dysfunction
  rationale: >-
    The germline DEPDC5 allele is necessary but frequently insufficient for
    disease: a large cohort found dominant inheritance from an asymptomatic parent
    in 64% of probands, illustrating markedly reduced penetrance. The determinants
    of who among carriers becomes affected (a focal somatic second hit, additional
    modifier variants, or environmental triggers) are not established, and this
    directly limits genetic counseling.
  evidence:
  - reference: PMID:30093711
    reference_title: The landscape of epilepsy-related GATOR1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were dominantly inherited from an asymptomatic parent in 64%
      (29/45) of the probands, illustrating the reduced penetrance of GATOR1
      variants.
    explanation: >-
      Quantifies the incomplete penetrance that this knowledge gap seeks to
      explain.
  proposed_experiments:
  - experiment_id: exp_depdc5_penetrance_somatic_screen
    name: Deep-sequencing screen for brain-somatic second hits across affected vs unaffected carriers
    description: >-
      In carriers with epilepsy versus unaffected relatives carrying the same
      germline DEPDC5 variant, use high-depth sequencing of resected/biopsy brain
      tissue (or surrogate tissues) to test whether a focal brain-somatic second
      hit, additional modifier variants, or mTORC1-pathway polygenic background
      distinguishes affected from unaffected carriers.
    experiment_type:
      preferred_term: genetic modifier and somatic-variant association study
    model_systems:
    - name: Carrier cohort with paired germline and brain-tissue sequencing
      description: >-
        Families segregating a DEPDC5 germline variant with both affected and
        unaffected carriers, with access to resected epileptogenic tissue where
        available.
      experimental_model_type: OTHER
- discussion_id: gap_depdc5_two_hit_universality
  prompt: >-
    Does the germline-plus-brain-somatic two-hit model account for all DEPDC5
    focal cortical dysplasia (and nonlesional focal epilepsy), or do some lesions
    arise from germline haploinsufficiency alone or other second-hit routes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Brain-Somatic Second-Hit Biallelic DEPDC5 Loss
  - pathophysiology#Dysmorphic Neurons and Focal Cortical Dysplasia
  rationale: >-
    The two-hit model is proven as a proof of concept in resected human tissue,
    with a mosaic gradient peaking at the seizure-onset zone, but somatic second
    hits are not detected in every DEPDC5 FCD case and nonlesional carriers have
    seizures without visible dysplasia. Whether biallelic loss is universally
    required for the lesion, or whether haploinsufficiency alone (or an
    undetected/undetectable somatic event) suffices, remains unresolved.
  evidence:
  - reference: PMID:29708508
    reference_title: Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a biallelic 2-hit - brain somatic and germline - mutational mechanism in
      DEPDC5 causes focal epilepsy with FCD
    explanation: >-
      Establishes the two-hit model as proof of concept while leaving its
      universality across DEPDC5 cases open.
  proposed_experiments:
  - experiment_id: exp_depdc5_two_hit_prevalence
    name: Systematic somatic second-hit detection across DEPDC5 FCD and nonlesional cortex
    description: >-
      Apply ultra-deep and single-nucleus sequencing to a large series of resected
      DEPDC5 epileptogenic specimens (both FCD-positive and MRI-normal) to quantify
      the fraction harboring a detectable brain-somatic second hit and correlate
      mutant allele fraction with histopathology severity.
    experiment_type:
      preferred_term: somatic variant prevalence study
    model_systems:
    - name: DEPDC5 surgical tissue biobank
      description: >-
        Resected epileptogenic cortex from germline DEPDC5 carriers spanning FCD
        and nonlesional phenotypes.
      experimental_model_type: OTHER
- discussion_id: hmm_depdc5_mtor_inhibitor_human_efficacy
  prompt: >-
    Does mTORC1 inhibition (sirolimus/everolimus) modify seizures or epileptogenesis
    in humans with DEPDC5-related epilepsy, as it does in Depdc5-loss mouse models,
    or is the preclinical rescue not translatable?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Constitutive mTORC1 Hyperactivation
  rationale: >-
    Chronic mTORC1 inhibition rescues behavioral and biochemical deficits in
    neuronal Depdc5-knockout mice, providing strong model-organism support for a
    precision-therapy rationale. However, controlled human evidence that mTOR
    inhibitors reduce seizures or SUDEP risk in DEPDC5 carriers is lacking, and
    focal biallelic-loss lesions may respond differently from a global germline
    knockout; translational validity is therefore the open question.
  evidence:
  - reference: PMID:31174205
    reference_title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Collectively, our data provide the first evidence of behavioral alterations
      in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic
      strategy for DEPDC5-related epilepsy in humans
    explanation: >-
      Model-organism evidence for mTOR-inhibitor rescue whose human translational
      validity is the mismatch to be resolved.
  proposed_experiments:
  - experiment_id: exp_depdc5_mtor_inhibitor_trial
    name: Controlled trial of mTOR inhibition in DEPDC5/GATOR1 drug-resistant focal epilepsy
    description: >-
      Conduct a controlled clinical trial (or well-powered n-of-1 series) of
      sirolimus or everolimus in genetically confirmed DEPDC5 drug-resistant focal
      epilepsy, with seizure frequency, EEG, and pharmacodynamic mTORC1 (pS6)
      readouts as endpoints, to test whether the mouse rescue translates to humans.
    experiment_type:
      preferred_term: interventional clinical trial
    model_systems:
    - name: DEPDC5 drug-resistant focal epilepsy cohort
      description: >-
        Genetically confirmed DEPDC5 carriers with drug-resistant focal epilepsy
        who are not immediate surgical candidates.
      experimental_model_type: OTHER

📚

References & Deep Research

References

6

PMID:23542697

Mutations in DEPDC5 cause familial focal epilepsy with variable foci.

No top-level findings curated for this source.

PMID:29708508

Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.

No top-level findings curated for this source.

PMID:30093711

The landscape of epilepsy-related GATOR1 variants.

No top-level findings curated for this source.

PMID:27066565

Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation.

No top-level findings curated for this source.

PMID:31174205

Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.

No top-level findings curated for this source.

CGGV:assertion_82a82c75-f9a5-4f51-a15c-6513c13df57c-2018-08-07T040000.000Z

DEPDC5 / focal epilepsy (Definitive)

No top-level findings curated for this source.

DEPDC5-Related Epilepsy

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References