Human Gene Module / Chromosome 2 / PLCD4

PLCD4phospholipase C delta 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
4 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
2q35
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the PLCD4 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA analysis of 4,504 ASD trios and 3,012 unaffected control/siblings trios from trio-based exome/genome sequencing studies identified PLCD4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019).

Molecular Function

This gene encodes a member of the delta class of phospholipase C enzymes. Phospholipase C enzymes play a critical role in many cellular processes by hydrolyzing phosphatidylinositol 4,5-bisphosphate into two intracellular second messengers, inositol 1,4,5-trisphosphate and diacylglycerol.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PLCD4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism Du Y , et al. (2019) Yes -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.295C>T p.Arg99Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.990G>C p.Gly330%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1558A>G p.Ile520Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2092_2095dup p.Leu699HisfsTer10 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant in the PLCD4 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA analysis of 4,504 ASD trios and 3,012 unaffected control/siblings trios from trio-based exome/genome sequencing studies identified PLCD4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019).

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

A de novo missense variant in the PLCD4 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA analysis of 4,504 ASD trios and 3,012 unaffected control/siblings trios from trio-based exome/genome sequencing studies identified PLCD4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo missense variant in the PLCD4 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA analysis of 4,504 ASD trios and 3,012 unaffected control/siblings trios from trio-based exome/genome sequencing studies identified PLCD4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
4

Increased from to 4

Description

A de novo missense variant in the PLCD4 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo frameshift variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA analysis of 4,504 ASD trios and 3,012 unaffected control/siblings trios from trio-based exome/genome sequencing studies identified PLCD4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019).

Krishnan Probability Score

Score 0.48928778130491

Ranking 6526/25841 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 8.116392604442E-9

Ranking 16246/18225 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 0.13887542743204

Ranking 81/18665 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 -0.2531888495831

Ranking 16428/20870 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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