Human Gene Module / Chromosome 14 / PRKD1

PRKD1Protein kinase D1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
9 / 0
Aliases
PRKD1, PKC-MU,  PKCM,  PKD,  PRKCM
Associated Syndromes
Rett syndrome
Chromosome Band
14q12
Associated Disorders
DD/NDD, EPS
Relevance to Autism

Three patients with atypical Rett syndrome were found to have a de novo 14q12 deletion that included the PRKD1 gene, but not the neighboring FOXG1 gene (Ellaway et al., 2012). Gene expression analysis demonstrated a decrease in both FOXG1 and PRKD1 mRNA expression levels in two of these patients. However, no pathogenic mutations in PRKD1 were identified following screening of an additional 32 patients with atypical Rett syndrome.

Molecular Function

The protein encoded by this gene is a serine/threonine protein kinase involved in many cellular processes, including Golgi body membrane integrity and transport, cell migration and differentiation, MAPK8/JNK1 and Ras pathway signaling, MAPK1/3 (ERK1/2) pathway signaling, cell survival, and regulation of cell shape and adhesion.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PRKD1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype Ellaway CJ , et al. (2012) No DD, epilepsy
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Zhang Y et al. (2023) Yes DD, ID
7 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 22968132 Ellaway CJ , et al. (2012)
c.919A>G p.Asn307Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1385A>G p.Tyr462Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2219G>A p.Arg740Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.41_71del p.Leu14ProfsTer34 frameshift_variant De novo - - 37035742 Zhang Y et al. (2023)
c.1321C>T p.Arg441Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1876C>T p.Arg626Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.896T>G p.Leu299Arg missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.2737_2738insA p.Leu913HisfsTer3 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Three patients with atypical Rett syndrome were found to have a de novo 14q12 deletion that included the PRKD1 gene, but not the neighboring FOXG1 gene (Ellaway et al., 2012). Gene expression analysis demonstrated a decrease in both FOXG1 and PRKD1 mRNA expression levels in two of these patients. However, no pathogenic mutations in PRKD1 were identified following screening of an additional 32 patients with atypical Rett syndrome.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

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

Three patients with atypical Rett syndrome were found to have a de novo 14q12 deletion that included the PRKD1 gene, but not the neighboring FOXG1 gene (Ellaway et al., 2012). Gene expression analysis demonstrated a decrease in both FOXG1 and PRKD1 mRNA expression levels in two of these patients. However, no pathogenic mutations in PRKD1 were identified following screening of an additional 32 patients with atypical Rett syndrome.

Reports Added
[New Scoring Scheme]
1/1/2016
S
icon
S

Score remained at S

Description

Three patients with atypical Rett syndrome were found to have a de novo 14q12 deletion that included the PRKD1 gene, but not the neighboring FOXG1 gene (Ellaway et al., 2012). Gene expression analysis demonstrated a decrease in both FOXG1 and PRKD1 mRNA expression levels in two of these patients. However, no pathogenic mutations in PRKD1 were identified following screening of an additional 32 patients with atypical Rett syndrome.

Reports Added
[14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
Krishnan Probability Score

Score 0.5779959197746

Ranking 619/25841 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 2.1262400507096E-5

Ranking 13855/18225 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 0.60990173410432

Ranking 742/18665 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 0.10100374871811

Ranking 6121/20870 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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