Human Gene Module / Chromosome 8 / PRKDC

PRKDCprotein kinase, DNA-activated, catalytic polypeptide

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
17 / 0
Aliases
PRKDC, DNA-PKcs,  DNAPK,  DNPK1,  HYRC,  HYRC1,  IMD26,  XRCC7,  p350
Associated Syndromes
-
Chromosome Band
8q11.21
Associated Disorders
DD/NDD, EPS
Relevance to Autism

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013). Two non-synonymous postzygotic mosaic mutations (PZMs) in the PRKDC gene were identified in ASD probands (one previously identified variant from Iossifov et al., 2014, and a novel variant in Lim et al., 2017); comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected genome-wide based on background rates (2/571 observed vs. 30/84,448 expected; hypergeometric P-value 0.018).

Molecular Function

This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) and functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. Homozygous or compound heterozygous mutations in the PRKDC gene are responsible for immunodeficiency 26, with or without neurologic abnormalities (IMD26; OMIM 615966)

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PRKDC (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation PRKDC mutations in a SCID patient with profound neurological abnormalities Woodbine L , et al. (2013) No DD, epilepsy, microcephaly
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary Unexpected role of interferon-? in regulating neuronal connectivity and social behaviour Filiano AJ , et al. (2016) No -
4 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
5 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
6 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.778-3T>C - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.1777-710dup - intron_variant Unknown - Simplex 23722905 Woodbine L , et al. (2013)
c.10530C>T p.Ala3510%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.396T>A p.Ile132= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1156G>A p.Val386Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1204A>G p.Thr402Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8636G>C p.Cys2879Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3364+1G>T - splice_site_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.7056G>A p.Gln2352%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.10414T>C p.Ile3472Thr missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.11841C>T p.Ser3947%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1078T>C p.Ser360Pro missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1115C>T p.Pro372Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2561G>T p.Arg854Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4427A>G p.His1476Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.8729G>A p.Arg2910His missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.10721C>T p.Ala3574Val missense_variant Familial Maternal;unknown Simplex 23722905 Woodbine L , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
4/1/2019
4
icon
4

Decreased from 4 to 4

Description

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
7/1/2016
icon
4

Increased from to 4

Description

SCID mice, which are homozygous for the severe combined immune deficiency (SCID) spontaneous mutation Prkdcscid, were shown to exhibit social deficits and hyper-connectivity between mutiple brain regions that could be rescued by repopulation of the adaptive immune system (Filiano et al., 2016). Three novel de novo predicted damaging missense variants in PRKDC were observed in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). A SCID patient with compound heterozygous variants in PRKDC was also found to exhibit dysmorphic features, severe growth failure, microcephaly, seizures, and developmental delay (Woodbine et al., 2013).

Krishnan Probability Score

Score 0.32990167301191

Ranking 24908/25841 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.
Original Source
ExAC Score

Score 1

Ranking 7/18225 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
Original Source
Sanders TADA Score

Score 0.68962929366356

Ranking 1094/18665 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).
Original Source
Zhang D Score

Score 0.27805629082819

Ranking 3068/20870 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.
Original Source
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