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

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• Pathogenic variants in the P21-activated kinase 1 (PAK1) gene are associated with neurodevelopmental and neurodegenerative disorders.
• The precise mechanisms linking PAK1 gene mutations to these disorders are not fully understood, hindering therapeutic development.
• PAK1 plays a crucial role in neuronal signaling and function, making its variants significant for brain development.

Purpose of the Study:

• To report a novel de novo PAK1 variant (c.396C>A, p.Asn132Lys) identified in a patient with Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD).
• To expand the known phenotypic spectrum of PAK1-related disorders.
• To review and synthesize existing literature on PAK1 variants and their associated clinical features and pathogenic mechanisms.

Main Methods:

• Trio exome sequencing was performed to identify and confirm the novel de novo variant.
• Clinical data from the affected patient was collected and analyzed.
• A comprehensive literature review of PAK1 variants was conducted.

Main Results:

• A likely pathogenic de novo PAK1 variant (c.396C>A, p.Asn132Lys) was identified in a 5-year-old girl with IDDMSSD, presenting with intellectual disability, speech delay, macrocephaly, hypotonia, gait ataxia, autism-like behaviors, and seizures.
• The identified variant was absent in parental DNA and population databases.
• The literature review summarized clinical features and pathogenic mechanisms of previously reported PAK1 variants.

Conclusions:

• The novel PAK1 variant expands the phenotypic spectrum of PAK1-related neurodevelopmental disorders.
• This finding highlights the critical role of the PAK1 autoinhibitory domain in neurodevelopment.
• Accurate identification of PAK1 variants is crucial for diagnosis, genotype-phenotype correlation, and development of targeted therapies for rare pediatric neurodevelopmental disorders.