Abstracts

In this study, 5 patients were identified with 5 de novo PAK1 variants, including p.Ile312Ser, p.Asp407Asn, p.Met453Thr, p.Leu470Pro, and p.Ile476Thr. All variants were missense, and one of which was a mosaic variant (Leu470Pro). 80% (4/5) patients with PAK1 variants had epilepsy, the seizure types included focal seizures, generalized tonic clonic seizures (GTCS) and epileptic spasms. One of patient diagnosed with infantile epileptic spasms syndrome (IESS). And four patients had macrocephaly. The last one patient only had mild to moderate DD and normal head circumference. All missense variants identified in this study were predicted to be “damaging” by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. Notably, the variants (Asp407Asn) associated with mild phenotypes had increased hydrogen bonds with ATP. Spatial and temporal expression analysis showed that PAK1 had three peak expressions in infant, adolescent and early adult brain subregions. Collectively, in our study (n=5) and published studies (n=11), all variants were missense. PAK1-related disorders encompass a wide phenotypic spectrum, including macrocephaly, epilepsy and DD/ID. Seizures were observed in 81.25% (13/16) of patients, and 53.8% (7/13) patients with epilepsy had fever sensitivity.

All variants of PAK1-related disorders were missense variants, five novel variants were included, and Leu470Pro was the first reported mosaic variant in PAK1. PAK1-related disorders encompass a wide phenotypic spectrum, including macrocephaly, epilepsy and DD/ID. IESS is a rare newly recognized phenotype of PAK1-related epilepsy. More than half of patients with epilepsy had fever sensitivity.