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DEPDC5-Related Epilepsy

, PhD and , MD, PhD.

Author Information

Initial Posting: .

Summary

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. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), and infantile spasms. Although psychomotor development is usually normal, intellectual disability or autism spectrum disorder has been reported in some individuals.

Diagnosis/testing.

The diagnosis of DEPDC5-related epilepsy is established in a proband with focal epilepsy and identification of a heterozygous pathogenic variant in DEPDC5 on molecular genetic testing.

Management.

Treatment of manifestations: The response to antiepileptic drugs (AEDs) is variable. While some individuals respond well to first-line AEDs, others are more refractory to treatment. There is currently no evidence that seizures respond better to one particular AED. In patients with focal cortical dysplasia, the possibility of epilepsy surgery should be explored early in the disease course.

Surveillance: Serial EEGs are appropriate when seizure frequency increases or when seizures of new symptomatology occur. Repeat brain MRI with a higher resolution technique is recommended in individuals with treatment-resistant seizures whose first brain MRI was normal.

Genetic counseling.

DEPDC5-related epilepsy is inherited in an autosomal dominant manner. Although de novo DEPDC5 pathogenic variants have been reported, the overall proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with DEPDC5-related epilepsy is at a 50% risk of inheriting the DEPDC5 pathogenic variant. Once the DEPDC5 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

Diagnosis

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

DEPDC5-related epilepsy comprises a spectrum of phenotypes characterized by focal epilepsy with variable foci that may or may not be associated with the presence of cortical brain malformations.

Suggestive Findings

DEPDC5-related epilepsy should be suspected in individuals with the following epilepsy features, seizure types, and/or epilepsy syndromes.

Epilepsy features

  • Focal epilepsy (emerging from any cortical region)
  • Age of seizure onset ranging from infancy to adulthood
  • Drug resistance rate that is usually higher than in other focal epilepsies

Seizure types

  • Focal seizures
  • Nocturnal seizures are common.
  • Infantile spasms can be seen.

Epilepsy syndromes

  • In families with a history of focal epilepsy, seizures can arise from different cortical areas in different family members, consistent with the phenotype of familial focal epilepsy with variable foci (FFEVF).
  • Smaller families can have a diagnosis of:
    • Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
      OR (more rarely)
    • Familial mesial temporal lobe epilepsy (FMTLE) or autosomal dominant epilepsy with auditory features (ADEAF)

Other features

  • Neurologic examination and laboratory tests are usually normal.
  • Psychomotor development and cognition are usually normal; however, some individuals with intellectual disability and/or neuropsychiatric problems have been described.
  • Background EEG is usually normal. Interictal EEG shows focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time in a given individual.
  • Hypsarrhythmia has been reported in one individual.
  • Brain MRI is normal or may show evidence of focal cortical dysplasia, hemimegalencephaly, or polymicrogyria.

Establishing the Diagnosis

The diagnosis of DEPDC5-related epilepsy is established in a proband with focal epilepsy and identification of a heterozygous pathogenic variant in DEPDC5 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of DEPDC5 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes genes associated with focal epilepsy (e.g., DEPDC5, NPRL2, NPRL3, CHRNA4, CHRNB2, CHRNA2, KCNT1) may also be considered.
    Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the relevant gene at the most reasonable cost while limiting secondary findings.

Table 1.

Molecular Genetic Testing Used in DEPDC5-Related Epilepsy

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
DEPDC5Sequence analysis 370/70 4
Gene-targeted deletion/duplication analysis 5None reported to date
1.
2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: 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 most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia. Most affected individuals have a family history of focal epilepsy.

Epilepsy Phenotype

Familial focal epilepsy with variable foci (FFEVF). DEPDC5-related epilepsy was initially described in families with FFEVF [Dibbens et al 2013, Ishida et al 2013]. FFEVF is characterized by focal seizures that arise from different cortical regions of the brain in different members of a family. Each individual in the family has, however, one specific focal seizure type. FFEVF is, therefore, a diagnosis at the level of the family, not at the level of the individual.

Age of seizure onset ranges from infancy to adulthood, and seizure symptomatology depends on the focal region of the brain in which 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 stay constant in a given individual.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) may be observed in some smaller families [Ishida et al 2013, Picard et al 2014]. In ADNFLE, family members have clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures.

Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years.

Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur.

Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent frontal onset. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.

The diagnosis of ADNFLE is made on clinical grounds. A detailed history from the affected individual and witnesses (supplemented if necessary by video-EEG monitoring) is the key to diagnosis.

Familial temporal lobe epilepsy. Rare nuclear families with temporal lobe seizures have been described. Two temporal lobe epilepsy syndromes are distinguished depending on the region of onset:

  • Familial mesial temporal lobe epilepsies (FMTLEs) are 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 convulsions preceding focal seizures. Two families with DEPDC5-related FMTLE have been reported [Ishida et al 2013].
  • 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 benign syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. Although truncating DEPDC5 pathogenic variants were found in two unrelated probands with epilepsy with auditory features, the overall phenotype in both families was not that of ADEAF as relatives with seizures had other types of focal epilepsy [Pippucci et al 2015]. In addition, one proband initially reported as part of a family with FMTLE developed seizures with auditory aura later in life [Striano et al 2015].

The nuclear families with DEPDC5-related FMTLE and those with ADEAF may actually have DEPDC5-related FFEVF that was not recognized due to small family size. Thus, while a heterozygous DEPDC5 pathogenic variant can be found in persons with seizures with auditory features, to date a heterozygous DEPDC5 pathogenic variant has 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 four unrelated individuals [Carvill et al 2015]. Focal seizures occurred later in three. Two had focal cortical dysplasia. Hypsarrhythmia was only reported in one of these individuals.

SUDEP. In one family with DEPDC5-related epilepsy, two family members died of sudden unexpected death in epilepsy (SUDEP) [Nascimento et al 2015]. In an exome-based analysis, six of 61 individuals with SUDEP were found to have pathogenic or possibly pathogenic variants in DEPDC5 [Bagnall et al 2016]; however, the finding did not reach statistical significance. Further evidence is needed to determine whether individuals with DEPDC5-related epilepsy are at increased risk for SUDEP.

Benign rolandic epilepsy has been reported in three individuals [Lal et al 2014]. However, two individuals had missense variants that in a subsequent in vitro study were shown to be unlikely to affect protein function [van Kranenburg et al 2015]. Further evidence is needed to confirm the role of DEPDC5 missense variants in benign rolandic epilepsy.

Other

Focal cortical dysplasia (FCD), a developmental cortical malformation characterized by cortical dyslamination and/or the presence of dysmorphic neurons or balloon cells, is the most common brain malformation reported in DEPDC5-related epilepsy [Scheffer et al 2014, Baulac et al 2015, D'Gama et al 2015, Scerri et al 2015, Ricos et al 2016].

Surgical resection may be required (see Management).

Brain malformations. A few individuals with seizures and hemimegalencephaly [D'Gama et al 2015, Mirzaa et al 2016] and one individual with focal epilepsy and bilateral symmetric perisylvian polymicrogyria [Ricos et al 2016] have been reported.

Psychomotor development and behavior. Although psychomotor development is usually normal, in some families individuals with intellectual disability or autism spectrum disorder have been described [Dibbens et al 2013, Ricos et al 2016].

All but one individual reported with infantile spasms had some degree of developmental delay [Carvill et al 2015].

EEG is usually normal or shows focal epileptic abnormalities. In individuals with infantile spasms, hypsarrhythmia can be seen.

Brain MRI is normal in most individuals; however, some individuals have had a malformation of cortical development detected on MRI and/or histopathologic examination [Scheffer et al 2014, Baulac et al 2015, D'Gama et al 2015, Scerri et al 2015, Mirzaa et al 2016, Ricos et al 2016, Weckhuysen et al 2016]. Most reported individuals had a focal cortical dysplasia type IIa or IIb associated with early-onset drug-resistant seizures.

One French family with a germline DEPDC5 variant (p.Arg422Ter) included an individual with focal cortical dysplasia with an additional somatic mosaic DEPDC5 variant in dysplastic brain tissue [Baulac et al 2015].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been described, although to date missense variants have been reported mostly in small families of individuals with apparently non-lesional epilepsies.

All individuals with brain malformations (focal cortical dysplasia or hemimegalencephaly) had nonsense or frameshift variants leading to a premature stop codon [Scheffer et al 2014, Baulac et al 2015, D'Gama et al 2015, Scerri et al 2015, Ricos et al 2016, Weckhuysen et al 2016].

Within a single family, a pathogenic variant in DEPDC5 can lead to variable phenotypic manifestations, including differences in age of seizure onset, seizure type, seizure severity, drug response, and presence of cortical malformations.

For review see Baulac [2016].

Penetrance

Asymptomatic heterozygotes are common in families with DEPDC5-related epilepsy.

Penetrance is reduced and may be as low as 60% [Dibbens et al 2013, Ishida et al 2013].

Nomenclature

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

Prevalence

To date more than 70 unrelated probands with DEPDC5-related epilepsy have been reported.

The prevalence of DEPDC5-related epilepsy varies among reported studies:

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.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Molecular genetic testing reveals a heterozygous pathogenic variant in CHRNA4, CHRNB2, CHRNA2, KCNT1, or DEPDC5 in approximately 20% of individuals with a family history of ADNFLE and fewer than 5% of individuals with no family history of ADNFLE (for review see Baulac [2014], Steinlein [2014]).

Compared to the frontal lobe seizures in ADNFLE caused by pathogenic variants in the genes encoding the ACh receptor (CHRNA4, CHRNB2, and CHRNA2), frontal lobe seizures in DEPDC5-related ADNFLE occur more frequently during wakefulness and less in clusters [Picard et al 2014].

Individuals with ADNFLE caused by pathogenic variants in KCNT1 more frequently have associated neuropsychiatric problems and/or intellectual disability [Heron et al 2012].

Cortical malformations have only been described in patients with DEPDC5-related ADNFLE [Baulac et al 2015].

NPRL2- and NPRL3-related focal epilepsy. The proteins NPRL2 and NPRL3, together with DEPDC5, form a complex called GATOR1 (GAP activity towards rags) complex. Germline heterozygous pathogenic variants in NPRL2 and NPRL3 have been described in individuals with a phenotypic spectrum resembling that of DEPDC5-related epilepsy [Korenke et al 2016, Ricos et al 2016, Sim et al 2016, Weckhuysen et al 2016]. Pathogenic variants are identified in familial focal epilepsies including families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) or familial focal epilepsy with variable foci (FFVEF), of which some family members can have a focal cortical dysplasia. Both inherited and de novo variants have been described. To date no differences in phenotype have been described between individuals with variants in NPRL2, NPRL3, or DEPDC5.

Autosomal dominant epilepsy with auditory features (ADEAF), previously called autosomal dominant partial epilepsy with auditory features (ADPEAF) or autosomal dominant lateral temporal lobe epilepsy (ADTLE), is a focal epilepsy syndrome in which auditory symptoms and/or receptive aphasia are prominent ictal manifestations. Affected individuals have focal seizures with or without altered consciousness; the most typical features are auras consisting of humming or buzzing, or more complex auditory hallucinations. Most affected individuals also have secondarily generalized seizures, but these are rare. The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy [Bisulli et al 2004].

The diagnosis of ADEAF is established by clinical findings, family history, and normal brain MRI or CT. A heterozygous pathogenic variant in LGI1 has been identified in approximately one third of affected families [Nobile et al 2009]. A heterozygous likely pathogenic variant in RELN has been identified in seven affected families [Dazzo et al 2015].

Familial mesial temporal lobe epilepsy (FMTLE) (OMIM 600512, 608096, 611630, 611631, 614417, 615697, 616461). The genetic etiology of FMTLE is heterogeneous: linkage to several different loci has been described. A small proportion of these families have a heterozygous pathogenic variant in DEPDC5 [Ishida et al 2013] (see Clinical Description).

Focal cortical dysplasia (FCD) caused by somatic mosaic pathogenic variants in other genes of the mTOR pathway. Recently, mosaic variants in the gene encoding mechanistic target of rapamycin (MTOR) have been identified in resected brain tissue of individuals with FCD [Leventer et al 2015, Lim et al 2015, Nakashima et al 2015, Mirzaa et al 2016].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DEPDC5-related epilepsy, the following evaluations are recommended:

  • Detailed clinical history to establish seizure type and frequency
  • Routine EEG
  • High-resolution brain MRI to evaluate for focal cortical dysplasia or other cortical malformation
  • Cognitive and behavioral assessment when problems are suspected based on focused medical history
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The response to antiepileptic drugs (AEDs) is variable. While some individuals respond well to first-line AEDs, others are more refractory to treatment. In four families with ADNFLE with a heterozygous DEPDC5 pathogenic variant, seven of nine individuals were drug resistant [Picard et al 2014], whereas in previous studies of individuals with ADNFLE, only one third of individuals were drug resistant.

There is currently no evidence that seizures respond better to one particular AED.

Attention should be paid to possible (long-term) side effects of AEDs. As in all patients with epilepsy, the goal should be to use as few AEDs as possible, in the lowest efficacious dose.

In patients with focal cortical dysplasia, the possibility of epilepsy surgery should be explored early in the disease course. 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]. Several of these individuals were part of a larger family in which most family members had a history of focal epilepsy without FCD.

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Surveillance

Serial EEGs are appropriate when seizure frequency increases or when seizures of new symptomatology occur.

Repeat brain MRI with a higher resolution technique is recommended in individuals with treatment-resistant seizures whose first brain MRI was normal.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Since loss-of-function variants in DEPDC5 are thought to lead to increased activation of the mTORC1 pathway, mTORC1 inhibitors including rapamycin (or everolimus) have been proposed as a potential targeted treatment option. So far, the clinical use of mTORC1 inhibitors has only been studied in the more severe mTORopathy tuberous sclerosis, caused by pathogenic variants in TSC1 or TSC2. Further studies are needed to determine whether (subsets of) patients with DEPDC5 could benefit from treatment with this class of drugs.

Search ClinicalTrials.gov 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DEPDC5-related epilepsy is inherited in an autosomal dominant manner.

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 has the DEPDC5 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The risk that sibs who inherit the pathogenic variant will be affected is less than 50% because of reduced penetrance (see Penetrance).
  • The sibs of a proband with clinically unaffected parents are still at increased risk for DEPDC5-related epilepsy because of the possibility of reduced penetrance in a parent.
  • If the DEPDC5 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with DEPDC5-related epilepsy is at a 50% risk of inheriting the DEPDC5 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a DEPDC5 pathogenic variant because of incomplete penetrance and variable expressivity.

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, his or her family members may be at risk.

Related Genetic Counseling Issues

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant disorder has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g with assisted reproduction) or undisclosed adoption could be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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.

  • American Epilepsy Society (AES)
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

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)

604364EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1; FFEVF1
614191DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5

Gene structure. DEPDC5 has 43 exons (NM_001242896.1) and spans 151 kb of genomic DNA. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic allelic variants. In total, 47 distinct pathogenic variants have been reported in more than 70 probands: 28 nonsense, 11 deletions, nine splice, and two insertions. Most variants lead to a premature stop codon and their transcripts are thought to be degraded by nonsense-mediated decay (NMD) as shown for the transcripts with p.Arg239Ter, p.Arg487Ter, and p.Arg1087Ter variants [Ishida et al 2013, Picard et al 2014]. A few recurrent variants have been reported (p.Arg422Ter, p.Arg487Ter, p.Arg843Ter, p.Trp1369Ter, p.Trp1466Ter).

See also Table 3 (pdf) for additional pathogenic variants.

Table 2.

DEPDC5 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.715C>Tp.Arg239TerNM_001242896​.1
NP_001229825​.1
c.1264C>Tp.Arg422Ter
c.1459C>Tp.Arg487Ter
c.2527C>Tp.Arg843Ter
c.3259C>Tp.Arg1087Ter
c.4397G>Ap.Trp1466Ter
c.4107G>Ap.Trp1369Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Allelic variants of uncertain significance (VUS). The functional significance (and therefore the pathogenicity) of missense variants remains to be demonstrated. As such, they are classified as variants of uncertain significance (VUS); see Table 3 (pdf). Classification of missense variants is less straightforward, and especially in individuals with rare phenotypes like infantile spasms, hemimegalencephaly, or polymicrogyria, additional evidence for pathogenicity of the variant is needed. Supportive features are segregation of the variant with a phenotype of focal epilepsy in familial cases, de novo occurrence in probands without a family history of epilepsy, or previous identification of the variant in other families with a compatible phenotype. That said, reduced penetrance and small family size tend to decrease the value of segregation analysis in the classification of missense variants.

Normal gene product. DEPDC5 encodes a ubiquitously expressed protein of 1603 amino acids consisting of a domain of unknown function (DUF) (amino acids 100-381) and a DEP domain (amino acid 1170-1251). In vitro and in yeast, 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 [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]. mTORC1 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].

Abnormal gene product. Most variants are likely to lead to a loss of function. Several nonsense variants have been shown to be targeted by NMD [Ishida et al 2013, Picard et al 2014].

Preliminary in vitro functional assessment 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].

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Chapter Notes

Author Notes

Dr Stéphanie Baulac is a researcher, head of a research team working on the genetics and physiopathology of familial focal epilepsies.

Dr Sarah Weckhuysen is a neurologist with a special interest in genetics of epilepsy.

To volunteer for research, please contact:

Stéphanie Baulac
Institut du Cerveau et de la Moelle épinière-ICM
Pitié-Salpêtrière Hospital
47 bd de l'Hôpital
75013 Paris, France
Email: rf.cmpu@caluab.einahpets

Revision History

  • 29 September 2016 (bp) Review posted live.
  • 23 December 2015 (sb) Original submission.
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