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Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Marked gene: PAK1 as ready
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Classified gene: PAK1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Added comment: Comment on list classification: Updated PAK1 from Amber to Green: Subsequent to the 8th August Webex, Konstantinos Varvagiannis left a Green review of PAK1 on the Epilepsy panel based on an additional 2019 paper (Horn et al, PMID:31504246). Green rating is supported by a new review by Helen Lord.
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.336 PAK1 Helen Lord edited their review of gene: PAK1: Added comment: Horn et al paper 2019 (31504246). 4 unrelated patients with intellectual disability, macrocephaly and seizures had de novo het missense variants in the PAK1 gene using trio exome sequencing. 3/4 of the patients reported as having seizures/focal epilepsy. 1/4 had one typical febrile seizure (age not known). All 4 variants located in important domains and are likely to lead to a gain of function.; Changed rating: GREEN; Changed publications: 31504246
Early onset or syndromic epilepsy v1.331 PAK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PAK1.
Early onset or syndromic epilepsy v1.330 PAK1 Rebecca Foulger Source NHS GMS was added to PAK1.
Early onset or syndromic epilepsy v1.320 PAK1 Rebecca Foulger Publications for gene: PAK1 were set to 30290153
Early onset or syndromic epilepsy v1.262 PAK1 Rebecca Foulger reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.261 PAK1 Helen Lord reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.260 PAK1 Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels:

Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.

(Previous review below); Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Classified gene: PAK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. 2 cases to date. Appears to be gain of function. Both missense variants.
Early onset or syndromic epilepsy v1.14 PAK1 Eleanor Williams Gene: pak1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.13 PAK1 Eleanor Williams commented on gene: PAK1
Early onset or syndromic epilepsy v1.1 PAK1 Konstantinos Varvagiannis gene: PAK1 was added
gene: PAK1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PAK1 were set to 30290153
Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158)
Penetrance for gene: PAK1 were set to unknown
Mode of pathogenicity for gene: PAK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PAK1 was set to AMBER
Added comment: Heterozygous pathogenic PAK1 variants cause Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158).

Harms et al. (PMID: 30290153) report on two unrelated individuals with de novo missense mutations in PAK1. Common features included developmental delay with associated intellectual disability, seizures, ataxic gait. Postnatal-onset microcephaly as well as some facial features were also common to both subjects.

Each patient was found to harbour a (private) de novo missense variant [NM_001128620.1:c.392A>G or p.(Tyr131Cys) - c.1286A>G or p.(Tyr429Cys)]. Expression studies demonstrated similar levels for the mutant and wt transcript and Western blot confirmed similar amounts of protein in patient fibroblasts when compared to controls. Functional studies suggest that gain-of-function is the underlying mechanism for both variants.

PAK1 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel as amber.
Sources: Literature