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Intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD) is characterized by global neurodevelopmental impairment, postnatal macrocephaly, epilepsy, and variable additional anomalies. PAK1 encodes p21-activated kinase 1, a serine/threonine kinase that modulates cytoskeletal dynamics via RAC1/CDC42 signaling. De novo heterozygous PAK1 variants have been implicated as a primary cause of IDDMSSD based on multiple independent reports and supportive functional data.
Genetic evidence for PAK1 in IDDMSSD derives from four unrelated probands with de novo missense variants in the autoinhibitory domain ([PMID:31504246]), three additional sporadic cases with phenotypic overlap ([PMID:32005903]), and one further individual harboring c.1409A>G (p.Leu470Gln) in the kinase domain ([PMID:36905087]), totalling eight probands. All variants occurred in highly conserved residues, with no familial segregation, consistent with an autosomal dominant, gain-of-function mechanism. There are no reports of transmitted cases or homozygous loss-of-function variants, underscoring the de novo origin and dominantly acting effect.
The variant spectrum comprises exclusively missense changes clustering in either the autoinhibitory CRIPaK domain (e.g., c.328T>A (p.Ser110Thr); c.361C>T (p.Pro121Ser); c.362C>T (p.Pro121Leu); c.397T>C (p.Ser133Pro); c.427A>G (p.Met143Val); c.428T>C (p.Met143Thr); c.428T>A (p.Met143Lys)) or within the protein kinase domain (c.1409A>G (p.Leu470Gln)). This recurrent residue involvement suggests domain-specific phenotypic correlations between regulatory vs kinase region variants.
Functional assessments support a gain-of-function mechanism. Structural modeling and in vitro kinase assays demonstrate that autosomal dominant PAK1 missense variants reduce autoinhibitory dimerization, increase monomerization, and enhance kinase activity leading to aberrant actin cytoskeleton regulation. Domain‐specific clustering correlates with differential phenotypes: variants in the autoregulatory region show more neuroanatomical features, whereas kinase domain changes associate with non-neurological comorbidities including hydrocephalus and horseshoe kidney ([PMID:36905087]).
No conflicting reports have been described; no studies refute the association or implicate alternative genes in the reviewed cohort. The collective data from eight de novo cases with coherent phenotypes and concordant functional results meet criteria for a strong gene–disease association.
Key Take-home: Heterozygous de novo PAK1 missense variants in the autoregulatory or kinase domains cause a gain-of-function dominant disorder manifesting as intellectual disability, postnatal macrocephaly, seizures, and structured comorbidities, providing a clear target for molecular diagnosis and potential future therapeutic modulation.
Gene–Disease AssociationStrongEight unrelated de novo PAK1 missense variants with consistent phenotype and functional concordance Genetic EvidenceStrongEight de novo heterozygous missense variants across unrelated individuals, clustering in regulatory and kinase domains Functional EvidenceModerateFunctional assays demonstrate impaired autoinhibition and kinase hyperactivation consistent with gain-of-function mechanism |