Intellectual disability - microarray and sequencing
Gene: PAK1Added missense tag: all variants published to-date are missense (PMID:30290153, PMID:31504246).Created: 21 Sep 2019, 8:29 a.m. | Last Modified: 21 Sep 2019, 8:29 a.m.
Panel Version: 2.1042
Comment on list classification: Updated rating from Amber to Green based on the additional 2019 paper reviewed by Konstantinos Varvagiannis. PMID:31504246 (Horn et al. 2019) report 4 unrelated individuals (2 Caucasian, 1 Moroccon, 1 Sephardi Jew). All 4 had developmental delay and moderate-profound ID amongst their phenotypes. All had novo missense PAK1 pathogenic variants: Leu470Arg, Ser133Pro, Pro121Ser, Ser110Thr. None of the variants were reported in gnomAD and all were predicted to be pathogenic. Two cases were previously reported in PMID:30290153 (Harms et al., 2018) and therefore this takes the total number over the threshold for a diagnostic-grade rating.Created: 21 Sep 2019, 8:19 a.m. | Last Modified: 21 Sep 2019, 8:19 a.m.
Panel Version: 2.1040
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, 3:09 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, 3:07 p.m.
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, 10:25 a.m. | Last Modified: 31 Aug 2019, 10:27 a.m.
Panel Version: 2.1021
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: LiteratureCreated: 13 Dec 2018, 9:39 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
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Variants in this GENE are reported as part of current diagnostic practice
Tag missense tag was added to gene: PAK1.
Phenotypes for gene: PAK1 were changed from Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158) to Intellectual developmental disorder with macrocephaly, seizures, and speech delay, 618158
Publications for gene: PAK1 were set to 30290153
Gene: pak1 has been classified as Green List (High Evidence).
Gene: pak1 has been classified as Amber List (Moderate Evidence).
gene: PAK1 was added gene: PAK1 was added to Intellectual disability. 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