First reported case of an inherited PACS2 pathogenic variant with variable expression

Area of Science:

• Genetics
• Neurology
• Developmental Biology

Background:

• Mutations in the PACS2 gene are associated with early-infantile epileptic encephalopathy 66 (EIEE 66), characterized by neonatal epilepsy, cerebellar dysgenesis, and facial dysmorphisms.
• De novo pathogenic variants in PACS2 are considered the primary cause of EIEE 66.

Observation:

• A toddler boy presented with neonatal-onset seizures, developmental delay, hypotonia, facial dysmorphisms, and cerebellar abnormalities including cisterna magna prominence and mild cerebellar hypoplasia.
• Genetic analysis revealed a known pathogenic PACS2 missense variant (p.Glu209Lys) in the affected child.

Findings:

• The identified PACS2 variant was inherited from the child's mother, who exhibited a milder clinical presentation.
• This represents the first reported instance of an inherited pathogenic PACS2 variant, expanding the known clinical spectrum of PACS2-related disorders.
• The case demonstrates variable expressivity, with a severe phenotype in the son and a mild phenotype in the mother.

Implications:

• Inherited PACS2 variants can cause a spectrum of neurological and developmental disorders.
• Understanding the inheritance patterns and variable expressivity of PACS2 variants is crucial for accurate genetic counseling and diagnosis.
• Further research into PACS2 function may elucidate mechanisms underlying neurodevelopmental and epileptic disorders.