Human Gene Module / Chromosome 11 / PAK1

PAK1p21 (RAC1) activated kinase 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
13 / 0
Aliases
PAK1, IDDMSSD,  PAKalpha
Associated Syndromes
-
Chromosome Band
11q13.5-q14.1
Associated Disorders
ADHD, ASD
Relevance to Autism

De novo missense variants in the PAK1 gene have been identified in patients presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, seizures, macrocephaly, and behavioral problems, including autism or autistic features (Harms et al., 2018; Kernohan et al., 2019; Horn et al., 2019).

Molecular Function

This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology.

External Links
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Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PAK1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder Harms FL , et al. (2018) No Macrocephaly
2 Primary p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy Kernohan KD , et al. (2019) Yes Developmental regression, macrocephaly
3 Recent Recommendation De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures Horn S , et al. (2019) No ASD or autistic features, ADHD, macrocephaly
4 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism Breuss MW , et al. (2019) Yes -
5 Support - Brunet T et al. (2021) No -
6 Support - Zhou X et al. (2022) Yes -
7 Support - et al. () No ASD, ADHD
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.427A>G p.Met143Val missense_variant De novo - - 37820543 et al. ()
c.428T>A p.Met143Lys missense_variant De novo - - 37820543 et al. ()
c.428T>C p.Met143Thr missense_variant De novo - - 37820543 et al. ()
c.338C>T p.Thr113Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.328T>A p.Ser110Thr missense_variant De novo - - 31504246 Horn S , et al. (2019)
c.361C>T p.Pro121Ser missense_variant De novo - - 31504246 Horn S , et al. (2019)
c.397T>C p.Ser133Pro missense_variant De novo - - 31504246 Horn S , et al. (2019)
c.1409T>G p.Leu470Arg missense_variant De novo - - 31504246 Horn S , et al. (2019)
c.392A>G p.Tyr131Cys missense_variant De novo - - 30290153 Harms FL , et al. (2018)
c.1286A>G p.Tyr429Cys missense_variant De novo - - 30290153 Harms FL , et al. (2018)
c.427A>G p.Met143Val missense_variant De novo - - 31873310 Breuss MW , et al. (2019)
c.362C>T p.Pro121Leu missense_variant De novo - - 31392718 Kernohan KD , et al. (2019)
c.1427T>C p.Ile476Thr missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

De novo missense variants in the PAK1 gene have been identified in patients presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, seizures, macrocephaly, and behavioral problems, including autism or autistic features (Harms et al., 2018; Kernohan et al., 2019; Horn et al., 2019).

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."

1/1/2021
S
icon
S

Score remained at S

Description

De novo missense variants in the PAK1 gene have been identified in patients presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, seizures, macrocephaly, and behavioral problems, including autism or autistic features (Harms et al., 2018; Kernohan et al., 2019; Horn et al., 2019).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
1/1/2020
S
icon
S

Score remained at S

Description

De novo missense variants in the PAK1 gene have been identified in patients presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, seizures, macrocephaly, and behavioral problems, including autism or autistic features (Harms et al., 2018; Kernohan et al., 2019; Horn et al., 2019).

Reports Added
[Autism risk in offspring can be assessed through quantification of male sperm mosaicism.2019]
10/1/2019
icon
S

Score remained at S

New Scoring Scheme
Description

De novo missense variants in the PAK1 gene have been identified in patients presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, seizures, macrocephaly, and behavioral problems, including autism or autistic features (Harms et al., 2018; Kernohan et al., 2019; Horn et al., 2019).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49144326794387

Ranking 5556/25841 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 0.67097012335813

Ranking 4640/18225 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 0.93289536642601

Ranking 12111/18665 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 0.34873309173606

Ranking 2025/20870 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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