# PAK1 (p21-Activated Kinase 1) and Its Role in Neurodevelopmental Disorders—New Case Report and a Comprehensive Review

## TL;DR

A new PAK1 gene variant is reported in a child with neurodevelopmental issues, expanding understanding of how this gene affects brain development and disease.

## Contribution

A novel de novo PAK1 variant is identified and linked to a specific neurodevelopmental disorder, expanding the known phenotypic spectrum.

## Key findings

- A 5-year-old girl with IDDMSSD was found to have a novel PAK1 variant, c.396C>A (p.Asn132Lys), absent in her parents and population databases.
- The variant is located in the autoinhibitory domain of PAK1, suggesting its role in neurodevelopmental pathogenesis.
- A literature review of PAK1 variants is provided, summarizing clinical features and mechanisms across autoregulatory and kinase domains.

## Abstract

Pathogenic variants in the PAK1 gene are linked to neurodevelopmental and neurodegenerative disorders by disrupting neuronal signaling and function. Despite increasing recognition, the mechanisms underlying these conditions remain incompletely understood, limiting therapeutic options. Here, we report a novel de novo PAK1 variant, c.396C>A (p.Asn132Lys), in a 5-year-old girl with Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). The patient presented with mild intellectual disability, delayed speech, macrocephaly, hypotonia, gait ataxia, autism-like behaviors, and focal epileptiform activity. Trio exome sequencing confirmed the variant as likely pathogenic, absent in her parents and population databases. This finding expands the phenotypic spectrum of PAK1-related disorders and underscores the critical role of the autoinhibitory domain in neurodevelopment. In addition, we performed a comprehensive literature review of PAK1 variants affecting both the autoregulatory and kinase domains, summarizing associated clinical features and pathogenic mechanisms. Our study highlights the importance of identifying PAK1 pathogenic variants for accurate diagnosis, refined genotype-phenotype correlations, and the development of potential targeted therapeutic strategies. By integrating novel case data with existing literature, this work advances understanding of PAK1-related neurodevelopmental disorders and supports the application of genetic analysis in rare pediatric NDD cases.