Human Gene Module / Chromosome 22 / DEPDC5

DEPDC5DEP domain containing 5

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
91 / 0
Aliases
DEPDC5, LL22NC03-113A11.1,  DEP.5
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
22q12.2-q12.3
Associated Disorders
SCZ, ASD, ID
Relevance to Autism

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD.

Molecular Function

Unknown function; shared homology with G protein signaling molecules and neuronal localization suggest a role in neuronal signal transduction.

Reports related to DEPDC5 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Dibbens LM , et al. (2013) No ASD, ID, SCZ, OCD
2 Support Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Ishida S , et al. (2013) No -
3 Support Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Scheffer IE , et al. (2014) No ASD, ID
4 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No -
5 Support Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dys... Burger BJ , et al. (2017) Yes -
6 Recent Recommendation DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons. Iffland PH 2nd , et al. (2018) No -
7 Support Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. de Calbiac H , et al. (2018) No -
8 Support Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic Network Development. Swaminathan A , et al. (2018) No -
9 Recent Recommendation The landscape of epilepsy-related GATOR1 variants. Baldassari S , et al. (2018) No ASD or autistic features
10 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No -
11 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
12 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders. Gao C , et al. (2019) No -
13 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
Rare Variants   (91)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Simplex 30093711 Baldassari S , et al. (2018)
- - copy_number_loss Unknown - Multiplex 30093711 Baldassari S , et al. (2018)
c.2170+11G>A - synonymous_variant De novo NA - 31452935 Feliciano P et al. (2019)
- - copy_number_loss Unknown - Multi-generational 30093711 Baldassari S , et al. (2018)
- - copy_number_loss Familial Paternal Not simplex 30093711 Baldassari S , et al. (2018)
c.727C>T p.Arg243Ter stop_gained Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.4520-2A>G - splice_site_variant Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.1474C>T p.Arg492Ter stop_gained Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.2512C>T p.Arg838Ter stop_gained Unknown - Unknown 30093711 Baldassari S , et al. (2018)
c.2620C>T p.Arg874Ter stop_gained Unknown - Unknown 30093711 Baldassari S , et al. (2018)
- - frameshift_variant Familial Maternal Not simplex 30093711 Baldassari S , et al. (2018)
c.3802C>T p.Arg1268Ter stop_gained Unknown - Multiplex 23542697 Dibbens LM , et al. (2013)
c.3802C>T p.Arg1268Ter stop_gained Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.4674G>A p.Trp1558Ter stop_gained Unknown - Unknown 30093711 Baldassari S , et al. (2018)
c.3536+4A>G - splice_region_variant Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.1936dup p.Ser646LysfsTer20 frameshift_variant De novo NA - 31178897 Gao C , et al. (2019)
c.3859G>A p.Val1287Met missense_variant Familial Paternal - 30945278 Jiao Q , et al. (2019)
c.3311C>T p.Ser1104Leu missense_variant Familial Paternal - 31139143 Long S , et al. (2019)
c.2485C>T p.Arg829Ter stop_gained Unknown - Multiplex 30093711 Baldassari S , et al. (2018)
c.435G>A p.Trp145Ter stop_gained Unknown - Not simplex 30093711 Baldassari S , et al. (2018)
c.1114C>T p.Gln372Ter stop_gained Unknown - Not simplex 30093711 Baldassari S , et al. (2018)
c.1385A>G p.Tyr462Cys missense_variant Unknown - Simplex 30093711 Baldassari S , et al. (2018)
- - copy_number_loss Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.715C>T p.Arg239Ter stop_gained Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.856C>T p.Arg286Ter stop_gained Familial Maternal Simplex 30093711 Baldassari S , et al. (2018)
c.319C>T p.Gln107Ter stop_gained Familial Paternal Unknown 30093711 Baldassari S , et al. (2018)
c.3113C>A p.Thr1038Asn missense_variant De novo NA Simplex 30093711 Baldassari S , et al. (2018)
c.2994+1G>A - splice_site_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.1459C>T p.Arg487Ter stop_gained Familial Paternal Multiplex 23542697 Dibbens LM , et al. (2013)
c.2620C>T p.Arg874Ter stop_gained Familial Maternal Simplex 30093711 Baldassari S , et al. (2018)
c.2760C>A p.Tyr920Ter stop_gained Familial Maternal Simplex 30093711 Baldassari S , et al. (2018)
c.4397G>A p.Trp1466Ter stop_gained Familial Maternal Multiplex 23542697 Dibbens LM , et al. (2013)
c.3994C>T p.Arg1332Ter stop_gained Familial Maternal Simplex 30093711 Baldassari S , et al. (2018)
c.4031T>A p.Leu1344Ter stop_gained Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.727C>T p.Arg243Ter stop_gained Unknown - Multi-generational 30093711 Baldassari S , et al. (2018)
c.2527C>T p.Arg843Ter stop_gained Unknown - Multi-generational 30093711 Baldassari S , et al. (2018)
c.1454G>A p.Arg485Gln missense_variant Familial Maternal Multiplex 23542701 Ishida S , et al. (2013)
c.299del p.Val100GlyfsTer3 frameshift_variant Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.982C>T p.Arg328Ter stop_gained De novo NA Multi-generational 30093711 Baldassari S , et al. (2018)
c.3669+5G>A - splice_region_variant Unknown - Multi-generational 30093711 Baldassari S , et al. (2018)
c.542T>A p.Met181Lys missense_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.1165dup p.Arg389ProfsTer2 frameshift_variant Unknown - Simplex 30093711 Baldassari S , et al. (2018)
c.1474C>T p.Arg492Ter stop_gained Familial Maternal Multi-generational 30945278 Jiao Q , et al. (2019)
c.2989C>T p.Arg997Cys missense_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.2715G>T p.Trp905Cys missense_variant Familial Paternal Unknown 30093711 Baldassari S , et al. (2018)
c.3303+5G>C - splice_region_variant Familial Paternal Not simplex 30093711 Baldassari S , et al. (2018)
c.982C>T p.Arg328Ter stop_gained Familial Maternal Multi-generational 23542701 Ishida S , et al. (2013)
c.4175C>T p.Ala1392Val missense_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.1114C>T p.Gln372Ter stop_gained Familial Maternal Multi-generational 23542701 Ishida S , et al. (2013)
c.790del p.Arg264GlufsTer9 frameshift_variant Unknown - Not simplex 30093711 Baldassari S , et al. (2018)
c.4567C>T p.Gln1523Ter stop_gained Unknown (likely familial) - Multiplex 23542701 Ishida S , et al. (2013)
c.1663C>T p.Arg555Ter stop_gained Familial Unknown Multi-generational 23542697 Dibbens LM , et al. (2013)
c.3217A>C p.Ser1073Arg missense_variant Unknown Not parental Multiplex 23542697 Dibbens LM , et al. (2013)
c.2500C>T p.Arg834Ter stop_gained Familial Paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.418C>T p.Gln140Ter stop_gained Familial Maternal Extended multiplex 24585383 Scheffer IE , et al. (2014)
c.2783C>T p.Ala928Val missense_variant Familial Paternal Not simplex 30093711 Baldassari S , et al. (2018)
c.279+1G>A - splice_site_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.279+1G>A - splice_site_variant Unknown Not paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.3114_3118del p.Met1038IlefsTer112 frameshift_variant Familial Maternal - 27864847 Parrini E , et al. (2016)
c.1264C>T p.Arg422Ter stop_gained Familial Paternal Extended multiplex 30093711 Baldassari S , et al. (2018)
c.2512C>T p.Arg838Ter stop_gained Familial Maternal Extended multiplex 30093711 Baldassari S , et al. (2018)
c.1663C>T p.Arg555Ter stop_gained Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.1663C>T p.Arg555Ter stop_gained Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.2527C>T p.Arg843Ter stop_gained Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.2593C>T p.Arg865Ter stop_gained Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.3259C>T p.Arg1087Ter stop_gained Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.232del p.Arg78GlyfsTer2 frameshift_variant Unknown - Multi-generational 30093711 Baldassari S , et al. (2018)
c.1355C>T p.Ala452Val missense_variant Familial Maternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.3311C>T p.Ser1104Leu missense_variant Familial Paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.3507C>G p.Ser1169Arg missense_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.21C>G p.Tyr7Ter stop_gained Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.1310del p.Asn437MetfsTer21 frameshift_variant Familial Maternal Not simplex 30093711 Baldassari S , et al. (2018)
c.715C>T p.Arg239Ter stop_gained Familial Maternal and paternal Multi-generational 23542701 Ishida S , et al. (2013)
c.484-485del - inframe_deletion Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.2824_2839del p.Ala942ProfsTer38 frameshift_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.193+1G>A - splice_site_variant Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.422_423insCTGG p.Gly142TrpfsTer3 frameshift_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.4393del p.Glu1465LysfsTer100 frameshift_variant Familial Paternal Not simplex 30093711 Baldassari S , et al. (2018)
ENST00000400246:c.4636T>C p.Tyr1546His missense_variant Familial Paternal Multiplex 29075622 Burger BJ , et al. (2017)
c.1400_1401insGG p.Phe467LeufsTer51 frameshift_variant Familial Paternal Simplex 30093711 Baldassari S , et al. (2018)
c.232del p.Arg78GlyfsTer2 frameshift_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.4107G>A p.Trp1369Ter stop_gained Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.4397G>A p.Trp1466Ter stop_gained Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.4606C>T p.Gln1536Ter stop_gained Familial Maternal and paternal Multi-generational 23542697 Dibbens LM , et al. (2013)
c.3203_3207del p.Ala1068AspfsTer82 frameshift_variant Familial Maternal Not simplex 30093711 Baldassari S , et al. (2018)
c.378del p.Tyr127IlefsTer51 frameshift_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.1310del p.Asn437MetfsTer21 frameshift_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.4151_4152insC p.Glu1385Ter frameshift_variant Familial Maternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.943_944insG p.Asn315ArgfsTer4 frameshift_variant Familial Paternal Multi-generational 30093711 Baldassari S , et al. (2018)
c.1122del p.Leu374PhefsTer30 frameshift_variant Familial Maternal and paternal Multi-generational 23542701 Ishida S , et al. (2013)
c.3631_3642delinsATACACCTCCAT p.Val1211_Leu1214delinsIleHisLeuHis inframe_indel Familial Maternal Simplex 30093711 Baldassari S , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD. A review of clinical and genetic data of 63 novel probands with epilepsy-related variants in the DEPDC5 gene found that ASD or autistic features were observed in 6/56 individuals (Baldassari and Baulac, 2018).

Score Delta: Score remained at S

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD. A review of clinical and genetic data of 63 novel probands with epilepsy-related variants in the DEPDC5 gene found that ASD or autistic features were observed in 6/56 individuals (Baldassari and Baulac, 2018).

7/1/2019
S
icon
S

Score remained at S

Description

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD. A review of clinical and genetic data of 63 novel probands with epilepsy-related variants in the DEPDC5 gene found that ASD or autistic features were observed in 6/56 individuals (Baldassari and Baulac, 2018).

4/1/2019
S
icon
S

Score remained at S

Description

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD. A review of clinical and genetic data of 63 novel probands with epilepsy-related variants in the DEPDC5 gene found that ASD or autistic features were observed in 6/56 individuals (Baldassari and Baulac, 2018).

7/1/2018
S
icon
S

Score remained at S

Description

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD. A review of clinical and genetic data of 63 novel probands with epilepsy-related variants in the DEPDC5 gene found that ASD or autistic features were observed in 6/56 individuals (Baldassari and Baulac, 2018).

10/1/2017
icon
S

Score remained at S

Description

Mutations in the DEPDC5 gene have been implicated in familial focal epilepsy with variable foci (FFEVF) and autosomal dominant focal epilepsies (Dibbens et al., 2013; Ishida et al., 2013; Scheffer et al., 2014). In one FFEVF family (A1) reported in Dibbens et al., 2013, three affected family members also had ASD, including one individual with ASD who had not had seizures. Scheffer et al., 2014 identified a maternally-inherited nonsense variant in the DEPDC5 gene in a family with 6 affected males presenting with focal epilepsy (family A); one of the affected males in this family also presented with severe intellectual disability and ASD.

Krishnan Probability Score

Score 0.44784155218769

Ranking 11936/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999993402596

Ranking 183/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.94746093957087

Ranking 17285/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 5

Ranking 279/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.37723866232075

Ranking 1704/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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