Human Gene Module / Chromosome 8 / PRKDC

PRKDCprotein kinase, DNA-activated, catalytic polypeptide

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
7 / 0
Aliases
PRKDC, DNA-PKcs,  DNAPK,  DNPK1,  HYRC,  HYRC1,  IMD26,  XRCC7,  p350
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
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)

Reports related to PRKDC (5 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 -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.10414T>C p.Ile3472Thr missense_variant De novo NA - 28714951 Lim ET , et al. (2017)
c.3364+1G>T - splice_site_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.1078T>C p.Ser360Pro missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.1115C>T p.Pro372Leu missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.2561G>T p.Arg854Ile missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.1777-710dup - intron_variant Familial Maternal;unknown Simplex 23722905 Woodbine L , et al. (2013)
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
3

Suggestive Evidence

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: Decreased from 4 to 3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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
[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).

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).

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.
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
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).
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.
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