U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

DEPDC5-Related Epilepsy

, PhD and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: March 9, 2023.

Estimated reading time: 31 minutes


Clinical characteristics.

DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals.


The diagnosis of DEPDC5-related epilepsy is established in a proband with suggestive findings and at least one heterozygous pathogenic variant in DEPDC5 identified by molecular genetic testing. Some affected individuals have biallelic variants in DEPDC5, and some have a second mosaic (or postzygotic) DEPDC5 variant within the brain.


Treatment of manifestations: The response to anti-seizure medication (ASM) is variable. While some individuals respond well to first-line ASMs, others are more refractory to treatment. There is currently no evidence that seizures respond better to one specific ASM. In individuals with hemimegalencephaly or focal cortical dysplasia and refractory epilepsy, resective epilepsy surgery should be explored early in the disease course. Standard treatment for developmental delay / intellectual disability and autism spectrum disorders.

Surveillance: Assess for new or ongoing neurologic manifestations (such as new-onset seizures or changes in seizure symptoms), predictive factors for sudden unexpected death in epilepsy, and developmental progress at each visit. Repeat EEG as appropriate when seizure frequency increases or when seizures of new symptomatology occur. Repeat brain MRI with a higher-resolution technique in individuals with treatment-resistant seizures whose first brain MRI was normal to rule out subtle cortical dysplasia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family.

Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of using ASM during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on ASM metabolism; and the effect of pregnancy on maternal seizure control.

Genetic counseling.

DEPDC5-related epilepsy is an autosomal dominant disorder; however, affected individuals with germline biallelic missense variants have been rarely reported. All probands reported to date with biallelic DEPDC5 variants inherited variants from their heterozygous parents. In these families, heterozygous parents may or may not have manifestations of DEPDC5-related epilepsy. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If one parent of the proband has a DEPDC5 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If both parents of a proband have a DEPDC5 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the DEPDC5 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

GeneReview Scope

DEPDC5-Related Epilepsy: Phenotypic Spectrum 1

Phenotypes 1Disorders
Epilepsy phenotypes
  • Familial focal epilepsy with variable foci (FFEVF)
  • Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (previously termed autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE])
  • Familial mesial temporal lobe epilepsy (FMTLE)
  • Autosomal dominant epilepsy with auditory features (ADEAF)
  • Infantile spasms
  • Developmental encephalopathy with macrocephaly and polymicrogyria
Brain malformation phenotypes
  • Focal cortical dysplasia
  • Hemimegalencephaly

For synonyms and outdated names, see Nomenclature.


For other genetic causes of these phenotypes, see Differential Diagnosis.


No consensus clinical diagnostic criteria for DEPDC5-related epilepsy have been published to date.

Suggestive Findings

DEPDC5-related epilepsy should be suspected in individuals with the following clinical, neuroimaging, EEG, and family history findings.

Clinical findings

  • Epilepsy (familial or sporadic), which may include:
    • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures
    • Nocturnal or sleep-related seizures
    • Drug-resistant epilepsy
    • Infantile spasms
  • Otherwise normal neurologic examination
  • Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely.
  • Sudden unexpected death in epilepsy

Neuroimaging/EEG findings

  • Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum)
    Note: A normal brain MRI does not preclude the diagnosis.
  • Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal.

Family history is typically consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations), although a few affected individuals have biallelic missense variants [Ververi et al 2023]. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of DEPDC5-related epilepsy is established in a proband with suggestive findings and at least one heterozygous pathogenic (or likely pathogenic) variant in DEPDC5 identified by molecular genetic testing (see Table 1). Some rare affected individuals have biallelic missense variants in DEPDC5.

Notes: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous DEPDC5 variant of uncertain significance does not establish or rule out the diagnosis of the disorder. (3) While most individuals with DEPDC5-related epilepsy have only a heterozygous germline (i.e., constitutional) pathogenic variant, some individuals with cortical malformations (most frequently focal cortical dysplasia or hemimegalencephaly) have been reported to have a brain-specific postzygotic (or mosaic) pathogenic variant in DEPDC5 on the non-mutated allele (i.e., a second pathogenic variant or "second hit") in addition to a heterozygous constitutional pathogenic variant (see Molecular Genetics).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. As the differential diagnosis for genetic causes of epilepsy and brain malformations is broad, single-gene testing (sequence analysis of DEPDC5, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Molecular genetic testing approaches typically include a multigene panel or comprehensive genomic testing (exome sequencing, genome sequencing).

Note: As some DEDPC5 pathogenic variants are postzygotic (or mosaic), deep sequencing of surgical resected brain tissue (from epilepsy surgery) could be considered in the diagnostic evaluation of an affected individual if there is a high suspicion for this condition and a surgical brain tissue resection is either planned or a brain tissue sample is available.

  • A multigene panel that includes genes associated with epilepsy with or without brain malformations (e.g., AKT3, CHRNA2, CHRNA4, CHRNB2, DEPDC5, KCNT1, MTOR, NPRL2, NPRL3, PIK3CA, PTEN, RHEB) may be considered. Notes: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) As brain-specific mosaic pathogenic variants of DEPDC5 have been identified in some individuals, the depth of sequencing of a multigene panel and sample type may determine the yield of molecular diagnostic testing using these panels.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. If no germline pathogenic variant is found in DEPDC5, sequence analysis with methods to detect somatic mosaicism could be considered (see above).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in DEPDC5-Related Epilepsy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
DEPDC5 Sequence analysis 3~96% 4
Gene-targeted deletion/duplication analysis 5~4% 4

See Molecular Genetics for information on variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While about 60% of individuals with DEPDC5-related epilepsy have a normal brain MRI [Baldassari et al 2019a], some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia type II or hemimegalencephaly. Most affected individuals have a family history of focal epilepsy.

To date, nearly 200 symptomatic individuals have been identified with a pathogenic variant in DEPDC5 [Dibbens et al 2013, Ishida et al 2013, Lal et al 2014, Martin et al 2014, Picard et al 2014, Scheffer et al 2014, Baulac et al 2015, Carvill et al 2015, D'Gama et al 2015, Nascimento et al 2015, Pippucci et al 2015, Scerri et al 2015, Striano et al 2015, Bagnall et al 2016, Ricos et al 2016, Weckhuysen et al 2016, Baldassari et al 2019b, Sim et al 2019, Krenn et al 2020, Liu et al 2020, Benova et al 2021, Wang et al 2021, Zhang et al 2021, Arenas-Cabrera et al 2022, Bacq et al 2022, Ververi et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

DEPDC5-Related Epilepsy: Frequency of Select Features in Symptomatic Individuals 1

FeatureFeature Subtype (if applicable)% of Persons w/Feature 2Comment
Epilepsy & related complications All types100% 3Most commonly frontal lobe seizures / sleep-related hypermotor epilepsy (30%)
Infantile spasms6%
Brain malformations All types20%
Focal cortical dysplasia17%Mostly type II
Polymicrogyria<1%One person was reported w/bilateral polymicrogyria. 4
Developmental/learning issues Developmental delays (language, motor)8%
Intellectual disability12%Most reported persons w/ID have FCD/focal epilepsy or drug-resistant epilepsy.
Developmental delay7%
Autism spectrum disorder5%

FCD = focal cortical dysplasia; SUDEP = sudden unexpected death in epilepsy


Asymptomatic heterozygotes are common in families with DEPDC5-related epilepsy. Penetrance is therefore reduced and may be as low as 60% [Dibbens et al 2013, Ishida et al 2013].


Percentages are based on nearly 200 reported symptomatic individuals with heterozygous pathogenic (or likely pathogenic) variants only and do not include individuals with biallelic pathogenic variants in DEPDC5.


Most symptomatic individuals are diagnosed because they have epilepsy, so this percentage is biased toward those individuals who have epilepsy as a feature.


Epilepsy. In general, the age of seizure onset can range from infancy to adulthood. However, not every person with a heterozygous pathogenic variant in DEPDC5 will develop epilepsy (see Penetrance). A variety of epilepsy phenotypes have been described in affected individuals/families.

  • Familial focal epilepsy with variable foci (FFEVF) is characterized by focal seizures that arise from different cortical regions of the brain in members of the same family. However, each affected individual in the family has one specific focal seizure type.
    • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate.
    • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen.
    • Age of onset, seizure frequency, and drug response may vary considerably within a family.
    • EEGs may show focal interictal abnormalities that typically stay constant in a given individual.
  • Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (lasting from a few seconds to a few minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures.
    • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years.
    • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur.
    • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region.
    • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent.
  • Familial temporal lobe epilepsy has rarely been described [Ishida et al 2013, Krenn et al 2020] and includes two subtypes.
    • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures.
    • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures.
      It is unclear if ADEAF is part of DEPDC5-related epilepsy. While a heterozygous DEPDC5 pathogenic variant can be found in individuals with seizures with auditory features, to date heterozygous DEPDC5 pathogenic variants have not been identified in larger families with the classic ADEAF phenotype [Bisulli et al 2016].
  • Infantile spasms have been reported as the initial seizure type in 10 unrelated individuals with DEPDC5 pathogenic variants [Carvill et al 2015, Tsang et al 2018, Baldassari et al 2019a, Lee et al 2019, Sim et al 2019], all but one of whom had some degree of developmental delay [Carvill et al 2015].
    • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia.
    • In individuals with infantile spasms, hypsarrhythmia can be seen.
  • Sudden unexpected death in epilepsy (SUDEP) has been described in about 10% of families with pathogenic germline heterozygous DEPDC5 variants in one study and has been reported in several individuals with DEPDC5-related epilepsy in case reports or small case series [Nascimento et al 2015, Bagnall et al 2016, Baldassari et al 2019a]. SUDEP may occur in heterozygous individuals without cognitive or developmental issue and without exposure to polytherapy. Therefore, affected individuals should be monitored regularly for known predictive factors of SUDEP, such as frequency of generalized tonic-clonic seizures (see Management) [Bacq et al 2022, Samanta 2022]. Further evidence from larger studies is needed to confirm to what extent individuals with DEPDC5-related epilepsy have an increased risk for SUDEP.

Neurodevelopment and behavior is usually normal, although a minority of affected individuals have been reported to have intellectual disability (ID) or autism spectrum disorder [Dibbens et al 2013, Ricos et al 2016, Baldassari et al 2019a], particularly if they have a history of infantile spasms or brain malformations. Individuals with ID who do not have infantile spasms typically have mild ID, while those with a history of infantile spasms have severe-to-profound ID.

Neuroimaging/histopathology. Brain MRI is normal in most individuals; however, about 20% of individuals have a cortical malformation detected on MRI and/or histopathologic examination [Scheffer et al 2014, Baulac et al 2015, D'Gama et al 2015, Mirzaa et al 2016, Ricos et al 2016, Weckhuysen et al 2016, Baldassari et al 2019a].

  • Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of dysmorphic neurons) associated with early-onset drug-resistant seizures.
  • Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals.
  • Other reported findings seen in a few individuals include the following:
    • Bilateral symmetric perisylvian polymicrogyria
    • Pachygyria
    • Subtle band heterotopia
    • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia

Biallelic pathogenic variants in DEPDC5. A more severe phenotype has been described in nine individuals with biallelic constitutional (non-mosaic) missense variants in DEPDC5 [Ververi et al 2023]. The phenotype consisted of progressive developmental encephalopathy, early-onset refractory epilepsy with multifocal seizures, bilateral polymicrogyria, and congenital macrocephaly. The presence of multisystemic features involving eye and cardiac defects has also been reported in these individuals.

Genotype-Phenotype Correlations

No definitive genotype-phenotype correlations have been identified.


Asymptomatic heterozygotes are common in families with DEPDC5-related epilepsy. Penetrance is therefore reduced and may be as low as 60% [Dibbens et al 2013, Ishida et al 2013].


Familial focal epilepsy with variable foci (FFEVF) [Dibbens et al 2013, Ishida et al 2013] was previously referred to as familial partial epilepsy with variable foci.


The prevalence of DEPDC5-related epilepsy is unknown. Nearly 200 unrelated probands with DEPDC5-related epilepsy have been reported to date.

Differential Diagnosis

The differential diagnosis for DEPDC5-related epilepsy includes other focal epilepsy syndromes as well as other genetic causes of (familial) focal epilepsy and focal cortical dysplasia (see Table 3). Of note, DEPDC5 is the most frequently involved gene among genetic focal epilepsies.

Table 3.

Genes of Interest in the Differential Diagnosis of DEPDC5-Related Epilepsy

Gene(s)DisorderMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/DEPDC5-related epilepsyDistinguishing from DEPDC5-related epilepsy
CHRNA2-, CHRNA4, CHRNB2-, & CRH-related ADSHEADFrontal lobe seizures 1Frontal lobe seizures in DEPDC5-related ADSHE occur more frequently during wakefulness & less frequently in clusters; no cortical malformations in CHRNA2-, CHRNA4, CHRNB2-, & CRH-related ADSHE to date. 2
KCNT1 KCNT1-related epilepsy ADEIMFS & ADSHEPersons w/KCNT1-related ADSHE are more likely to develop seizures at a younger age, have cognitive comorbidity, & display psychiatric & behavioral issues than those w/ADSHE from other causes.

LGI1- & RELN-related ADEAF 3ADFocal epilepsy syndrome in which auditory symptoms &/or receptive aphasia are prominent ictal manifestations. Affected persons have focal seizures ± altered consciousness; most typical features are auras consisting of humming or buzzing, or more complex auditory hallucinations. Most affected persons also have secondarily generalized seizures, but these are rare.ADEAF is more commonly assoc w/pathogenic variants in LGI1 & RELN than w/pathogenic variants in DEPDC5.
NPRL2- & NPRL3-related focal epilepsy (OMIM 617116 & 617118)ADFamilial focal epilepsies incl families w/ADSHE or FFEVF, of which some family members can have FCD type II 5NPRL2- & NPRL3-related epilepsies are similar to DEPDC5-related epilepsies. DEPDC5 & NPRL2/3 are part of the same complex, GATOR1, 4 a repressor of the amino acid-sensing branch of the mTOR pathway. To date, 35 persons have been reported w/NPRL2 or NPRL3 pathogenic variants.
MTOR FCD (OMIM 607341) & Smith-Kingsmore syndrome (OMIM 616638)AD or
Focal epilepsy, FCD type II, hemimegalencephaly, polymicrogyriaHyperpigmented macules, macrocephaly. Germline pathogenic MTOR variants cause Smith-Kingsmore syndrome. Persons w/germline MTOR pathogenic variants typically represent simplex cases (i.e., only affected family member). Somatic MTOR variants cause hemimegalencephaly & FCD.
AKT3 FCD, hemimegalencephaly, & AKT3-related megalencephaly-polydactyly-polymicrogyria-hydrocephalus syndrome 6AD or
Focal epilepsy, FCD type II, hemimegalencephaly, polymicrogyriaMacrocephaly, vascular malformations. Persons w/AKT3 pathogenic variants typically represent simplex cases (i.e., only affected family member).
PIK3CA PIK3CA-related overgrowth spectrum SomaticFocal epilepsy, FCD type II, hemimegalencephaly, polymicrogyriaMacrocephaly, somatic overgrowth, polydactyly, syndactyly, vascular/lymphatic malformations
RHEB FCD & hemimegalencephaly 7SomaticFocal epilepsy, FCD type II, hemimegalencephalySomatic mutations
PIK3C2B Focal epilepsy 8ADFocal epilepsyTo date, all persons w/PIK3C2B pathogenic variants have represented simplex cases (i.e., only affected family member).
PTEN 9Megalencephaly, hemimegalencephalySomaticFocal epilepsy, FCD type II, hemimegalencephalyMacrocephaly, overgrowth, hamartomas, familial cancer

AD = autosomal dominant; ADEAF = autosomal dominant epilepsy with auditory features; ADSHE = autosomal dominant sleep-related epilepsy; AR = autosomal recessive; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia; FFEVF = familial focal epilepsy with variable foci; MOI = mode of inheritance


Previously referred to as autosomal dominant partial epilepsy with auditory features (ADPEAF) or autosomal dominant lateral temporal lobe epilepsy (ADTLE) [Bisulli et al 2021]


NPRL2 and NPRL3, together with DEPDC5, form a complex called GATOR1 (GAP activity towards Rags) complex.



No clinical practice guidelines for DEPDC5-related epilepsy have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DEPDC5-related epilepsy, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with DEPDC5-Related Epilepsy

Neurologic Assessment by neurologist for eval of suspected seizures, as indicatedTo incl EEG & high-resolution brain MRI to evaluate for focal cortical dysplasia or other brain malformations
Assessment for predictive factors for SUDEP 1
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Genetic counseling By genetics professionals 2To inform affected persons & their families re nature, MOI, & implications of DEPDC5-related disorders to facilitate medical & personal decision making
Family support
& resources
Assess need for:

MOI = mode of inheritance; SUDEP = sudden unexpected death in epilepsy


Predictive factors may include frequent generalized clonic-tonic seizures.


Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

There is no specific cure for DEPDC5-related epilepsy.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see Table 5).

Table 5.

Treatment of Manifestations in Individuals with DEPDC5-Related Epilepsy

Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Brain malformations Resective epilepsy surgery may be considered in persons w/focal epilepsy that is refractory to medical therapy.
  • In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course.
  • Surgical outcomes have been variable. 2
Developmental delay /
Intellectual disability
Standard treatment, which may incl supportive developmental therapies (OT, PT, ST) to address specific delayed areasConsultation w/neurodevelopmental specialist may be considered.
Autism spectrum disorder Standard treatment, which may incl ABA therapy
Family/Community Ensure appropriate social work involvement to connect families w/local resources & support.

ABA = applied behavior analysis; ASM = anti-seizure medication; FCD = focal cortical dysplasia; OT = occupational therapy; PT = physical therapy; ST = speech therapy


Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.


In one study, four of five unrelated individuals who underwent epilepsy surgery with resection of the focal cortical dysplasia had a favorable postoperative outcome [Baulac et al 2015]. In contrast, another study reported a poor surgical outcome in four individuals [Benova et al 2021].


To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

Recommended Surveillance for Individuals with DEPDC5-Related Epilepsy

Neurologic Assess for new or ongoing manifestations, such as new-onset seizures &/or changes in seizures or tone.At each visit
Assess for predictive factors for SUDEP. 1
Repeat brain MRI (incl higher-resolution brain MRI).For those w/treatment-resistant seizures whose first brain MRI was normal
Repeat EEG.To address any ↑ in seizure frequency or new seizure symptomatology
Development Monitor developmental progress.At each visit
Family/Community Assess family need for social work support, care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

SUDEP = sudden unexpected death in epilepsy


Predictive factors may include frequent generalized clonic-tonic seizures.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for the development of seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medications (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Loss-of-function pathogenic variants in DEPDC5 lead to hyperactivation of the mTORC1 pathway (see Molecular Genetics). Therefore, mTORC1 inhibitors including rapamycin (or everolimus) have been proposed as a potential targeted treatment option. Animal model studies, notably Depdc5 knockout rodent models, have shown that mTOR inhibitors reduce the frequency of seizures [Marsan et al 2016, Ribierre et al 2018, Yuskaitis et al 2019]. So far, the clinical use of mTORC1 inhibitors has only been studied in the more severe mTORopathy tuberous sclerosis complex [Wiegand et al 2021], and in focal cortical dysplasia type II [Kato et al 2022] with mitigated results. Further studies are needed to determine whether (subsets of) individuals with DEPDC5 could benefit from treatment with this class of drugs.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DEPDC5-related epilepsy is typically inherited in an autosomal dominant manner. In rare cases autosomal recessive inheritance of missense variants has been reported in association with a severe multisystemic phenotype (five families, including three consanguineous families) [Ververi et al 2023].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the DEPDC5 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Reduced penetrance and intrafamilial variable expressivity are observed in DEPDC5-related epilepsy. Sibs who inherit a pathogenic variant:
    • May or may not have manifestations of DEPDC5-related epilepsy – asymptomatic heterozygotes are common in families with DEPDC5-related epilepsy, and penetrance may be as low as 60% (see Penetrance);
    • May have different phenotypic manifestations of DEPDC5-related epilepsy than other affected family members – the age of seizure onset, seizure type, seizure severity, drug response, and presence of cortical malformations can vary between affected family members (see Genotype-Phenotype Correlations).
  • If the DEPDC5 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Parental gonosomal mosaicism has been reported in one family [Baulac et al 2015].
  • If the parents have not been tested for the DEPDC5 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for DEPDC5-related epilepsy because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the DEPDC5 pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a DEPDC5 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a DEPDC5 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Heterozygous parents of a proband with autosomal recessive DEPDC5-related epilepsy may be at risk of developing epilepsy based on one report [Ververi et al 2023].

Sibs of a proband. If both parents are known to be heterozygous for a DEPDC5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Offspring of a proband. To date, it is unknown whether individuals with autosomal recessive severe DEPDC5-related epilepsy are able to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DEPDC5 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the DEPDC5 pathogenic variants in the family.

Related Genetic Counseling Issues

Predictive testing for autosomal dominant DEPDC5-related epilepsy. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the DEPDC5 pathogenic variant in the family.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the DEPDC5 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for DEPDC5-related epilepsy and preimplantation genetic testing are possible. Note, however, that the specific phenotype, age of onset, and disease severity cannot be accurately predicted on the basis of molecular genetic testing results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

DEPDC5-Related Epilepsy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for DEPDC5-Related Epilepsy (View All in OMIM)


Molecular Pathogenesis

DEPDC5 encodes a ubiquitously expressed protein of 1,603 amino acids, GATOR complex protein DEPDC5 (DEPDC5). The 3D structure was recently resolved and identified five domains (NTD, SABA, SHEN, DEP, and CTD) [Shen et al 2018]. DEPDC5 acts as a GTPase-activating protein for RagA/B and, together with NPRL2 and NPRL3, is part of the GATOR1 complex that inhibits the mechanistic target of the rapamycin complex 1 (mTORC1) pathway in response to low amino acid cellular levels [Bar-Peled et al 2013, Panchaud et al 2013]. A role of DEPDC5 in the signaling pathway has been confirmed in vivo in a Depdc5 knockout rat [Marsan et al 2016]. Rapamycin complex 1 has serine-threonine kinase activity that phosphorylates several downstream proteins, regulating essential cellular functions like protein synthesis, cell growth, migration, and proliferation [Lasarge & Danzer 2014, Liu & Sabatini 2020]. Most pathogenic variants are likely to lead to a loss of function. Several nonsense pathogenic variants have been shown to be targeted by nonsense-mediated mRNA decay [Ishida et al 2013, Picard et al 2014].

Preliminary in vitro functional studies investigated the effect on mTORC1 signaling of ten DEPDC5 variants identified in individuals with focal epilepsy: seven missense variants, two nonsense variants, and one in-frame deletion. The two nonsense variants and the 3-bp deletion clearly disrupted the DEPDC5-dependent inhibition of mTORC1, while none of the seven missense variants had this effect [van Kranenburg et al 2015].

Some individuals with cortical malformations (most frequently focal cortical dysplasia type II or hemimegalencephaly) have been reported to have a brain-specific mosaic (or postzygotic) pathogenic variant in DEPDC5 on the normal (or non-mutated) allele (i.e., a "second hit") in addition to a heterozygous constitutional pathogenic variant [Baulac et al 2015, D'Gama et al 2017, Ribierre et al 2018, Baldassari et al 2019b, Sim et al 2019, Lee et al 2020]. In addition, somatic copy-neutral loss of heterozygosity of the DEPDC5 non-mutated allele may also occur [Mirzaa et al 2016, Baldassari et al 2019b], leading to brain tissues with biallelic pathogenic DEPDC5 variants.

Mechanism of disease causation. Loss of function

DEPDC5-specific laboratory technical considerations – targeted testing for mosaicism. Sequence analysis of DNA derived from affected brain tissues (whether visibly affected or not) may detect a pathogenic variant that is not present in DNA isolated from peripheral blood or other peripheral tissues (e.g., saliva). Note: Sensitivity to detect low-level mosaicism of a mosaic pathogenic variant is greatest using next-generation sequencing in tissues other than blood and has a high yield when analyzing affected (brain) tissues in particular.

Chapter Notes

Author Notes

Dr Stéphanie Baulac is a neurogeneticist, research director, and group leader at ICM (Paris Brain Institute) working on the genetics and neurobiology of focal epilepsies with brain malformations.

Dr Sara Baldassari is a neurogeneticist and principal investigator working at the ICM (Paris Brain Institute) on the genetics and physiopathology of focal epilepsies with brain malformations.

To volunteer for research contact:

Stéphanie Baulac
Institut du Cerveau (ICM)-Paris Brain Institute
Pitié-Salpêtrière Hospital
47 bd de l'Hôpital
75013 Paris, France
Email: gro.etutitsni-mci@caluab.einahpets

Author History

Sara Baldassari, PhD (2023-present)
Stéphanie Baulac, PhD (2016-2023)
Sarah Weckhuysen, MD, PhD; Vlaams Instituut voor Biotechnologie (2016-2023)

Revision History

  • 9 March 2023 (gm) Comprehensive update posted live
  • 29 September 2016 (bp) Review posted live
  • 23 December 2015 (sb) Original submission


Literature Cited

  • Arenas-Cabrera C, Baena-Palomino P, Sánchez-García J, Oliver-Romero M, Chocrón-González Y, Caballero-Martínez M. Sleep-related hypermotor epilepsy with genetic diagnosis: description of a case series in a tertiary referral hospital. J Cent Nerv Syst Dis. 2022;14:11795735211060114. [PMC free article: PMC8844731] [PubMed: 35177946]
  • Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I, Picard F, Navarro V, Sisodiya SM, Baulac S, et al. Cardiac investigations in sudden unexpected death in DEPDC5-related epilepsy. Ann Neurol. 2022;91:101–16. [PMC free article: PMC9299146] [PubMed: 34693554]
  • Bagnall RD, Crompton DE, Petrovski S, Lam L, Cutmore C, Garry SI, Sadleir LG, Dibbens LM, Cairns A, Kivity S, Afawi Z, Regan BM, Duflou J, Berkovic SF, Scheffer IE, Semsarian C. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol. 2016;79:522–34. [PubMed: 26704558]
  • Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, Nordli DR Jr, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, Baulac S. The landscape of epilepsy-related GATOR1 variants. Genet Med. 2019a;21:398–408. [PMC free article: PMC6292495] [PubMed: 30093711]
  • Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S, Bulteau C, Dorison N, Fohlen M, Polivka M, Weckhuysen S, Dorfmüller G, Chipaux M, Baulac S. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol. 2019b;138:885–900. [PMC free article: PMC6851393] [PubMed: 31444548]
  • Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340:1100–6. [PMC free article: PMC3728654] [PubMed: 23723238]
  • Baulac S, Ishida S, Marsan E, Miquel C, Biraben A, Nguyen DK, Nordli D, Cossette P, Nguyen S, Lambrecq V, Vlaicu M, Daniau M, Bielle F, Andermann E, Andermann F, Leguern E, Chassoux F, Picard F. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77:675–83. [PubMed: 25623524]
  • Benova B, Sanders MWCB, Uhrova-Meszarosova A, Belohlavkova A, Hermanovska B, Novak V, Stanek D, Vlckova M, Zamecnik J, Aronica E, Braun KPJ, Koeleman BPC, Jansen FE, Krsek P. GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: a possible gradient in severity? Eur J Paediatr Neurol. 2021;30:88–96. [PubMed: 33461085]
  • Bisulli F, Licchetta L, Baldassari S, Pippucci T, Tinuper P. DEPDC5 mutations in epilepsy with auditory features. Epilepsia. 2016;57:335. [PubMed: 26849478]
  • Bisulli F, Rinaldi C, Pippucci T, Minardi R, Baldassari S, Zenesini C, Mostacci B, Fanella M, Avoni P, Menghi V, Caporali L, Muccioli L, Tinuper P, Licchetta L. Epilepsy with auditory features: contribution of known genes in 112 patients. Seizure. 2021;85:115–8. [PubMed: 33453592]
  • Carvill GL, Crompton DE, Regan BM, McMahon JM, Saykally J, Zemel M, Schneider AL, Dibbens L, Howell KB, Mandelstam S, Leventer RJ, Harvey AS, Mullen SA, Berkovic SF, Sullivan J, Scheffer IE, Mefford HC. Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet. 2015;1:e17. [PMC free article: PMC4807908] [PubMed: 27066554]
  • D'Gama AM, Geng Y, Couto JA, Martin B, Boyle EA, LaCoursiere CM, Hossain A, Hatem NE, Barry BJ, Kwiatkowski DJ, Vinters HV, Barkovich AJ, Shendure J, Mathern GW, Walsh CA, Poduri A. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol. 2015;77:720–5. [PMC free article: PMC4471336] [PubMed: 25599672]
  • D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM, Najm I, Ying Z, Yang E, Barkovich AJ, Kwiatkowski DJ, Vinters HV, Madsen JR, Mathern GW, Blümcke I, Poduri A, Walsh CA. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep. 2017;21:3754–66. [PMC free article: PMC5752134] [PubMed: 29281825]
  • Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-López R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg AM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546–51. [PubMed: 23542697]
  • Gozzelino L, Kochlamazashvili G, Baldassari S, Mackintosh AI, Licchetta L, Iovino E, Liu YC, Bennett CA, Bennett MF, Damiano JA, Zsurka G, Marconi C, Giangregorio T, Magini P, Kuijpers M, Maritzen T, Norata GD, Baulac S, Canafoglia L, Seri M, Tinuper P, Scheffer IE, Bahlo M, Berkovic SF, Hildebrand MS, Kunz WS, Giordano L, Bisulli F, Martini M, Haucke V, Hirsch E, Pippucci T. Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy. Brain. 2022;145:2313–31. [PMC free article: PMC9337808] [PubMed: 35786744]
  • Ishida S, Picard F, Rudolf G, Noé E, Achaz G, Thomas P, Genton P, Mundwiller E, Wolff M, Marescaux C, Miles R, Baulac M, Hirsch E, Leguern E, Baulac S. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45:552–5. [PMC free article: PMC5010101] [PubMed: 23542701]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Kato M, Kada A, Shiraishi H, Tohyama J, Nakagawa E, Takahashi Y, Akiyama T, Kakita A, Miyake N, Fujita A, Saito AM, Inoue Y. Sirolimus for epileptic seizures associated with focal cortical dysplasia type II. Ann Clin Transl Neurol. 2022;9:181–92. [PMC free article: PMC8862414] [PubMed: 35040598]
  • Korenke GC, Eggert M, Thiele H, Nürnberg P, Sander T, Steinlein OK. Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia. 2016;57:e60–3. [PubMed: 26786403]
  • Krenn M, Wagner M, Hotzy C, Graf E, Weber S, Brunet T, Lorenz-Depiereux B, Kasprian G, Aull-Watschinger S, Pataraia E, Stogmann E, Zimprich A, Strom TM, Meitinger T, Zimprich F. Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes. J Med Genet. 2020;57:624–33. [PubMed: 32086284]
  • Lal D, Reinthaler EM, Schubert J, Muhle H, Riesch E, Kluger G, Jabbari K, Kawalia A, Bäumel C, Holthausen H, Hahn A, Feucht M, Neophytou B, Haberlandt E, Becker F, Altmüller J, Thiele H, Lemke JR, Lerche H, Nürnberg P, Sander T, Weber Y, Zimprich F, Neubauer BA. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75:788–92. [PubMed: 24591017]
  • Lasarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci. 2014;7:18. [PMC free article: PMC3953715] [PubMed: 24672426]
  • Lee S, Kim SH, Kim B, Lee ST, Choi JR, Kim HD, Lee JS, Kang HC. Clinical implementation of targeted gene sequencing for malformation of cortical development. Pediatr Neurol. 2020;103:27–34. [PubMed: 31481326]
  • Lee WS, Baldassari S, Chipaux M, Adle-Biassette H, Stephenson SEM, Maixner W, Harvey AS, Lockhart PJ, Baulac S, Leventer RJ. Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia. Ann Clin Transl Neurol. 2021;8:485–90. [PMC free article: PMC7886042] [PubMed: 33434304]
  • Lee WS, Stephenson SEM, Howell KB, Pope K, Gillies G, Wray A, Maixner W, Mandelstam SA, Berkovic SF, Scheffer IE, MacGregor D, Harvey AS, Lockhart PJ, Leventer RJ. Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA. Ann Clin Transl Neurol. 2019;6:1338–44. [PMC free article: PMC6649645] [PubMed: 31353856]
  • Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21:183–203. [PMC free article: PMC7102936] [PubMed: 31937935]
  • Liu L, Chen ZR, Xu HQ, Liu DT, Mao Y, Liu HK, Liu XR, Zhou P, Lin SM, Li B, He N, Su T, Zhai QX, Meng H, Liao WP, Yi YH. DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect. Front Neurosci. 2020;14:821. [PMC free article: PMC7432260] [PubMed: 32848577]
  • Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: a review of the clinical literature. Am J Med Genet C Semin Med Genet. 2019;181:591–610. [PubMed: 31609537]
  • Marsan E, Ishida S, Schramm A, Weckhuysen S, Muraca G, Lecas S, Liang N, Treins C, Pende M, Roussel D, Le Van Quyen M, Mashimo T, Kaneko T, Yamamoto T, Sakuma T, Mahon S, Miles R, Leguern E, Charpier S, Baulac S. Depdc5 knockout rat: a novel model of mTORopathy. Neurobiol Dis. 2016;89:180–9. [PubMed: 26873552]
  • Martin C, Meloche C, Rioux MF, Nguyen DK, Carmant L, Andermann E, Gravel M, Cossette P. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet. 2014;86:570–4. [PubMed: 24283814]
  • Mirzaa GM, Campbell CD, Solovieff N, Goold C, Jansen LA, Menon S, Timms AE, Conti V, Biag JD, Adams C, Boyle EA, Collins S, Ishak G, Poliachik S, Girisha KM, Yeung KS, Chung BHY, Rahikkala E, Gunter SA, McDaniel SS, Macmurdo CF, Bernstein JA, Martin B, Leary R, Mahan S, Liu S, Weaver M, Doerschner M, Jhangiani S, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Shendure J, Saneto RP, Novotny EJ, Wilson CJ, Sellers WR, Morrissey M, Hevner RF, Ojemann JG, Guerrini R, Murphy LO, Winckler W, Dobyns WB. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73:836–45. [PMC free article: PMC4979321] [PubMed: 27159400]
  • Nascimento FA, Borlot F, Cossette P, Minassian BA, Andrade DM. Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation. Neurol Genet. 2015;1:e28. [PMC free article: PMC4811380] [PubMed: 27066565]
  • Panchaud N, Péli-Gulli MP, De Virgilio C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal. 2013;6:ra42. [PubMed: 23716719]
  • Picard F, Makrythanasis P, Navarro V, Ishida S, de Bellescize J, Ville D, Weckhuysen S, Fosselle E, Suls A, De Jonghe P, Vasselon Raina M, Lesca G, Depienne C, An-Gourfinkel I, Vlaicu M, Baulac M, Mundwiller E, Couarch P, Combi R, Ferini-Strambi L, Gambardella A, Antonarakis SE, Leguern E, Steinlein O, Baulac S. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82:2101–6. [PubMed: 24814846]
  • Pippucci T, Licchetta L, Baldassari S, Palombo F, Menghi V, D'Aurizio R, Leta C, Stipa C, Boero G, d'Orsi G, Magi A, Scheffer I, Seri M, Tinuper P, Bisulli F. Epilepsy with auditory features: A heterogeneous clinico-molecular disease. Neurol Genet. 2015;1:e5. [PMC free article: PMC4821078] [PubMed: 27066544]
  • Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, Hills LB, Heinzen EL, Hill A, Hill RS, Barry BJ, Bourgeois BF, Riviello JJ, Barkovich AJ, Black PM, Ligon KL, Walsh CA. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012;74:41–8. [PMC free article: PMC3460551] [PubMed: 22500628]
  • Ribierre T, Deleuze C, Bacq A, Baldassari S, Marsan E, Chipaux M, Muraca G, Roussel D, Navarro V, Leguern E, Miles R, Baulac S. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J Clin Invest. 2018;128:2452–8. [PMC free article: PMC5983335] [PubMed: 29708508]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, Licchetta L, Bisulli F, Bayly MA, Hughes J, Baldassari S, Palombo F., Epilepsy Electroclinical Study Group. Santucci M, Meletti S, Berkovic SF, Rubboli G, Thomas PQ, Scheffer IE, Tinuper P, Geoghegan J, Schreiber AW, Dibbens LM. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79:120–31. [PubMed: 26505888]
  • Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:467–85. [PMC free article: PMC4771397] [PubMed: 26966367]
  • Samanta D. DEPDC5-related epilepsy: a comprehensive review. Epilepsy Behav. 2022;130:108678. [PubMed: 35429726]
  • Scerri T, Riseley JR, Gillies G, Pope K, Burgess R, Mandelstam SA, Dibbens L, Chow CW, Maixner W, Harvey AS, Jackson GD, Amor DJ, Delatycki MB, Crino PB, Berkovic SF, Scheffer IE, Bahlo M, Lockhart PJ, Leventer RJ. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol. 2015;2:575–80. [PMC free article: PMC4435711] [PubMed: 26000329]
  • Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, Licchetta L, Provini F, Bisulli F, Vadlamudi L, Gecz J, Connelly A, Tinuper P, Ricos MG, Berkovic SF, Dibbens LM. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782–7. [PubMed: 24585383]
  • Shen K, Huang RK, Brignole EJ, Condon KJ, Valenstein ML, Chantranupong L, Bomaliyamu A, Choe A, Hong C, Yu Z, Sabatini DM. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature. 2018;556:64–9. [PMC free article: PMC5975964] [PubMed: 29590090]
  • Sim JC, Scerri T, Fanjul-Fernández M, Riseley JR, Gillies G, Pope K, van Roozendaal H, Heng JI, Mandelstam SA, McGillivray G, MacGregor D, Kannan L, Maixner W, Harvey AS, Amor DJ, Delatycki MB, Crino PB, Bahlo M, Lockhart PJ, Leventer RJ. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol. 2016;79:132–7. [PubMed: 26285051]
  • Sim NS, Ko A, Kim WK, Kim SH, Kim JS, Shim KW, Aronica E, Mijnsbergen C, Spliet WGM, Koh HY, Kim HD, Lee JS, Kim DS, Kang HC, Lee JH. Precise detection of low-level somatic mutation in resected epilepsy brain tissue. Acta Neuropathol. 2019;138:901–12. [PubMed: 31377847]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Striano P, Serioli E, Santulli L, Manna I, Labate A, Dazzo E, Pasini E, Gambardella A, Michelucci R, Striano S, Nobile C. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia. 2015;56:e168–71. [PubMed: 26216793]
  • Tsang MH, Leung GK, Ho AC, Yeung KS, Mak CC, Pei SL, Yu MH, Kan AS, Chan KY, Kwong KL, Lee SL, Yung AW, Fung CW, Chung BH. Exome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy. Epilepsia Open. 2018;4:63–72. [PMC free article: PMC6398105] [PubMed: 30868116]
  • van Kranenburg M, Hoogeveen-Westerveld M, Nellist M. Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. Hum Mutat. 2015;36:200–9. [PubMed: 25366275]
  • Ververi A, Zagaglia S, Menzies L, Baptista J, Caswell R, Baulac S, Ellard S, Lynch S, Consortium GER, Jacques TS, Chawla MS, Heier M, Kulseth MA, Mero IL, Våtevik AK, Kraoua I, Rhouma HB, Younes TB, Miladi Z, Turki IBY, Jones WD, Clement E, Eltze C, Mankad K, Merve A, Parker J, Hoskins B, Pressler R, Sudhakar S, DeVile C, Homfray T, Kaliakatsos M, Ponnudas PP, Robinson R, Keim SMB, Habibi I, Reymond A, Sisodiya SM, Hurst JA. Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria. Hum Mol Genet. 2023;32:580–94. [PMC free article: PMC9896472] [PubMed: 36067010]
  • Wang T, Wang J, Ma Y, Zhou H, Ding D, Li C, Du X, Jiang YH, Wang Y, Long S, Li S, Lu G, Chen W, Zhou Y, Zhou S, Wang Y. High genetic burden in 163 Chinese children with status epilepticus. Seizure. 2021;84:40–6. [PubMed: 33278787]
  • Weckhuysen S, Marsan E, Lambrecq V, Marchal C, Morin-Brureau M, An-Gourfinkel I, Baulac M, Fohlen M, Kallay Zetchi C, Seeck M, de la Grange P, Dermaut B, Meurs A, Thomas P, Chassoux F, Leguern E, Picard F, Baulac S. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia. 2016;57:994–1003. [PubMed: 27173016]
  • Wiegand G, May TW, Lehmann I, Stephani U, Kadish NE. Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies. Seizure. 2021;93:111–9. [PubMed: 34740140]
  • Yuskaitis CJ, Rossitto LA, Gurnani S, Bainbridge E, Poduri A, Sahin M. Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice. Hum Mol Genet. 2019;28:2952–64. [PMC free article: PMC6736288] [PubMed: 31174205]
  • Zhang X, Huang Z, Liu J, Li M, Zhao X, Ye J, Wang Y. Phenotypic and genotypic characterization of DEPDC5-related familial focal epilepsy: case series and literature review. Front Neurol. 2021;12:641019. [PMC free article: PMC8258162] [PubMed: 34239491]
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK385626PMID: 27683934


Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...