Human Gene Module / Chromosome 17 / PDK2

PDK2pyruvate dehydrogenase kinase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
4 / 0
Aliases
PDK2, PDHK2,  PDKII
Associated Syndromes
-
Chromosome Band
17q21.33
Associated Disorders
-
Relevance to Autism

De novo missense variants in the PDK2 gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2017) and one proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PDK2 as a gene with an excess of missense variants with CADD scores > 30 (false discovery rata < 5%, count >1) (Coe et al., 2018). Functional analysis of the ASD-associated p.Arg120Gln missense variant, which was originally identified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a loss-of-function effect (failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression).

Molecular Function

This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PDK2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
5 Support - Marcogliese PC et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1076A>C p.Tyr359Ser missense_variant De novo - - 28135719 et al. (2017)
c.95C>A p.Ser32Tyr missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.359G>A p.Arg120Gln missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.669+1G>A - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants in the PDK2 gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2017) and one proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PDK2 as a gene with an excess of missense variants with CADD scores > 30 (false discovery rata < 5%, count >1) (Coe et al., 2018).

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

De novo missense variants in the PDK2 gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2017) and one proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PDK2 as a gene with an excess of missense variants with CADD scores > 30 (false discovery rata < 5%, count >1) (Coe et al., 2018).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

De novo missense variants in the PDK2 gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2017) and one proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PDK2 as a gene with an excess of missense variants with CADD scores > 30 (false discovery rata < 5%, count >1) (Coe et al., 2018).

Reports Added
[New Scoring Scheme]
1/1/2019
icon
4

Increased from to 4

Description

De novo missense variants in the PDK2 gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2017) and one proband with an unspecified developmental disorder (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PDK2 as a gene with an excess of missense variants with CADD scores > 30 (false discovery rata < 5%, count >1) (Coe et al., 2018).

Krishnan Probability Score

Score 0.451610927332

Ranking 10633/25841 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 0.16897552451649

Ranking 7238/18225 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 0.82799909465783

Ranking 2799/18665 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 -0.076305946710867

Ranking 11425/20870 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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