p21 protein‐activated kinase 1 is associated with severe regressive autism, and epilepsy

The p21‐activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/β‐catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of β‐catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.