PAK3

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*PAK3* is located on chromosome Xq23 and encodes a serine/threonine protein kinase that acts as a downstream effector of the small GTPases CDC42 and RAC1. PAK3 plays a role in dendritic spine morphogenesis and synaptic plasticity by regulating the actin cytoskeleton. PAK3 can also exert kinase-independent functions and regulate transcription and postsynaptic transmission by acting as a scaffolding protein through its N-terminal, non-catalytic domain. *PAK3* was first reported in relation to X-linked non-syndromic intellectual disability in 1998 (Allen et al., PMID: 9731525) and was subsequently reported in individuals with intellectual disability, seizures and syndromic features, including variable dysmorphic features and brain abnormalities. Therefore, we chose to curate this gene for its relationship with X-linked complex neurodevelopmental disorder. The clinical features of affected males include global developmental delay, intellectual disability (varying from borderline to severe), speech impairment, and, in some individuals, mild dysmorphic features, small head or microcephaly, seizures, hypotonia, oro-motor impairment, and behavioral disorders (hyperactivity, aggressiveness, and autistic behavior). In some families, missense variants are associated with a more severe presentation, including brain malformations (agenesis of the corpus callosum, cerebellar hypoplasia, and hydrocephalus), and skin abnormalities (icthyosis). Female carriers are typically unaffected but some exhibit mild cognitive impairment. Thirteen variants (9 missense, 1 nonsense, 1 frameshift, 1 splice and 1 large deletion) that have been reported in 14 probands in 14 publications (PMIDs: 9731525, 10946356, 12884430, 17853471, 18523455, 24556213, 25533962, 25666757, 27753653, 28481730, 28126652, 29246092, 31843706, 41223971) are included in this curation. Variants in this gene segregated with disease in 29 additional family members. The variants occurred *de novo* in two probands and were maternally inherited in the remaining cases. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function, although it has been suggested that some variants may also exert dominant-negative or gain-of-function effects, which are still being characterized. Variants lead to loss of function due to variable mechanisms, including loss of catalytic activity, protein instability, altered activation by GTPases, reduced or modified binding affinities for PAK-interacting exchange factors (PIX) and NCK adaptor proteins, and disrupted ability to form heterodimers with PAK1. This gene-disease relationship is also supported by biochemical function, protein interactions, functional assays and mouse models. In summary, there is definitive evidence supporting the relationship between *PAK3* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Autism and Intellectual Disability Gene Curation Expert Panel on July 31, 2018. It was reevaluated on August 14, 2026 (SOP Version 12). Although new cases and experimental evidence were added, the classification did not change.

Inheritance Pattern: XL

Disease ID:MONDO:0010361

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010361

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0009022

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010361

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010361

Submitter: Labcorp Genetics (formerly Invitae)