Novel PAK1 variants related to a variable phenotypic spectrum ranging from mild developmental delay to infantile epileptic spasms syndrome.

OBJECTIVE

To identify the novel variants and explore the new phenotypes of patients with PAK1-related disorder.

METHODS

Five patients with PAK1 variants were identified by whole-exon sequencing. Damaging effects of variants were analyzed using protein modelling.

RESULTS

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), with a variant allele fraction of 13.4 % (13/97). Four of five patients with PAK1 variants had epilepsy, the seizure types included focal seizures, generalized tonic-clonic seizure and epileptic spasms. One patient diagnosed with infantile epileptic spasms syndrome (IESS). Four patients had macrocephaly. One patient only had mild developmental delay (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 variant Asp407Asn associated with a milder phenotype is predicted to have increased hydrogen bonds with ATP in contrast to our other reported variants. 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 variants. PAK1-related disorders encompass a wide phenotypic spectrum, including macrocephaly, epilepsy and DD/intellectual disability (ID). Seizures were observed in 81.25 % (13/16) of patients, and 53.8 % (7/13) patients with epilepsy had febrile seizure.

CONCLUSIONS

All variants of PAK1-related disorders were missense variants. In this study, five de novo 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 febrile seizure.