Human Gene Module / Chromosome 9 / PLAA

PLAAphospholipase A2 activating protein 

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
5 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9p21.2
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the PLAA gene (p.Ile609Thr) was identified in a male ASD proband from a simplex family from the MSSNG cohort in Yuen et al., 2007; functional assessment of this variant and a previously unreported ASD-associated missense variant in the PLAA gene (p.Leu795Met) in Iacomino et al., 2024 demonstrated that both missense variants affected the PLAA interactome and resulted in significantly reduced binding to VCP/p97. A de novo splice-region variant in this gene was also identified in an ASD proband from the Simons Simplex Collection (Zhou et al., 2022).

Molecular Function

Predicted to enable ubiquitin binding activity. Involved in cellular response to lipopolysaccharide; macroautophagy; and positive regulation of phospholipase A2 activity. Located in cytoplasm; extracellular exosome; and nucleus. Plays a role in protein ubiquitination, sorting and degradation through its association with VCP (Papadopoulos et al., 2017). Biallelic variants in the PLAA gene are responsible for neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA; OMIM 617527), an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profoundly impaired intellectual development and severely impaired or absent motor function (Falik Zaccai et al., 2017; Hall et al., 2017).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PLAA (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Chrisovalantis Papadopoulos et al. (2017) No -
2 Support - Tzipora C Falik Zaccai 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 Support - Emma A Hall et al. (2017) No -
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Primary - Michele Iacomino et al. (2024) Yes -
8 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1823-4A>G - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.16A>G p.Thr6Ala missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1826T>C p.Ile609Thr missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2383C>A p.Leu795Met missense_variant De novo - Simplex 38650658 Michele Iacomino et al. (2024)
c.240_241insTAG p.Tyr80_Pro81insTer frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
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.

7/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.44729500644493

Ranking 12906/25841 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 0.6486574984567

Ranking 4743/18225 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 0.93571015101721

Ranking 12963/18665 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 0.009087727101558

Ranking 8389/20870 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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