Early onset or syndromic epilepsy

Gene: PAK1

I don't know

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.

Created: 26 Sep 2019, 3:59 p.m. | Last Modified: 26 Sep 2019, 3:59 p.m.

Panel Version: 1.337

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

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.

Created: 23 Sep 2019, 1:22 p.m. | Last Modified: 23 Sep 2019, 1:22 p.m.

Panel Version: 1.336

AD IDDMSSD. Harms et al, 2018 (30290153) - 2 unrelated boys aged 7 and 5 with a similar neurodev disorderboth had seizures. Patient 1 - consang Arabian parents, patient 2 - unrelated Caucasian parents. De novo het missense variants identifed - Y131C and Y429C. Functional studies support pathogenicity.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 31504246

Comment on list classification: Changing rating from grey to amber. 2 cases to date. Appears to be gain of function. Both missense variants.

Created: 14 Feb 2019, 3:19 p.m.

PAK1 is associated with Intellectual developmental disorder with macrocephaly, seizures, and speech delay in OMIM. No data in Gene2Phenotype.

PMID: 30290153 (Harms et al (2018) - 2 unrelated patients with de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and c.1286A>G (p.Tyr429Cys). Patients presented with developmental delay, secondary macrocephaly, seizures, and ataxic gait. In fibroblasts of the two affected individuals, we observed a trend toward enhanced PAK1 kinase activity.

Created: 14 Feb 2019, 3:18 p.m.

Green List (high evidence)

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)

Created: 31 Aug 2019, 10:29 a.m. | Last Modified: 31 Aug 2019, 10:29 a.m.

Panel Version: 1.260

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 macrocephaly 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

Created: 13 Dec 2018, 9:41 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158)

Publications

• 30290153
• doi.org/10.1093/brain/awz264

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments