Human Gene Module / Chromosome 7 / PCLO

PCLOpiccolo presynaptic cytomatrix protein

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 11
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
7q21.11
Associated Disorders
-
Relevance to Autism

Multiple de novo variants in the PCLO gene, including two loss-of-function (LoF) variants and two potentially damaging missense variants, have been identified in ASD probands from the Autism Sequencing Consortium, the SPARK cohort, and the MSSNG cohort (Satterstrom et al., 2020; Zhou et al., 2022). A meta-analysis of genetic data from two schizophrenia cohorts combined with whole-exome sequencing data from the Autism Sequencing Consortium in Liu et al., 2023 identified PCLO as a shared risk gene for schizophrenia and ASD (P-value 5.8E-08). Both rare and common variants in the PCLO gene have previously been found to associate with schizophrenia, bipolar disorder, and major depressive disorder (Sullivan et al., 2009; Bochdanovits et al., 2009; Choi et al., 2011; Chen et al., 2021).

Molecular Function

The protein encoded by this gene is part of the presynaptic cytoskeletal matrix, which is involved in establishing active synaptic zones and in synaptic vesicle trafficking. An autosomal recessive form of pontocerebellar hypoplasia (PCH3; OMIM 608027) was found to be caused by a homozygous nonsense variant in the PCLO gene in a consanguineous Omani family in which affected individuals also presented with developmental delay and seizures (Ahmed et al., 2015).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PCLO (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Negative Association - Nabi R et al. (2003) Yes -
2 Positive Association - Sullivan PF et al. (2009) No -
3 Positive Association - Bochdanovits Z et al. (2009) No -
4 Positive Association - Choi KH et al. (2011) No -
5 Support - Seo S et al. (2013) No -
6 Support - Ahmed MY et al. (2015) No -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support - Nitta A et al. (2021) No -
9 Support - Chen CH et al. (2021) No -
10 Support - Zhou X et al. (2022) Yes -
11 Primary - Liu D et al. (2023) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1534C>T p.Gln512Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.5355A>T p.Leu1785Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11492G>A p.Arg3831His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11498A>C p.Tyr3833Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11912A>T p.Glu3971Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.13382G>A p.Arg4461Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.626dup p.Pro210SerfsTer12 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5892G>A p.Thr1964%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.12385A>G p.Lys4129Glu missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.13111A>G p.Met4371Val missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.9906G>A p.Gln3302%3D synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.14439A>T p.Thr4813%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.10624C>T p.Arg3542Ter stop_gained Familial Both parents Multiplex 25832664 Ahmed MY et al. (2015)
c.15425A>G p.His5142Arg missense_variant Unknown Not maternal Simplex 34834409 Chen CH et al. (2021)
c.4604C>T p.Ser1535Leu missense_variant Unknown Not maternal Multiplex 34834409 Chen CH et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

7/1/2023
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.61552730390077

Ranking 114/25841 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 0.99999999998893

Ranking 52/18225 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 0.95043251532055

Ranking 18490/18665 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 0.5725971291456

Ranking 167/20870 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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