Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• PACS1-neurodevelopmental disorder (PACS1-NDD) is an autosomal dominant intellectual disability disorder.
• Previously, a recurrent variation at Arg203 was considered diagnostic for PACS1-NDD.
• The proposed mechanism involves altered PACS1 protein affinity for client proteins.

Observation:

• A novel PACS1 variant (p.(Ser252Phe)) was identified in a mother and daughter with overlapping PACS1-NDD features.
• This variant impedes the binding of PACS1 to the GGA3 adaptor protein.
• The identified variant is distinct from the previously known Arg203 variation.

Findings:

• The novel p.(Ser252Phe) variant in the PACS1 gene is associated with syndromic intellectual disability.
• This finding suggests that disrupting PACS1 binding to GGA3 is a pathogenic mechanism for intellectual disability.
• The study expands the known spectrum of PACS1-related neurodevelopmental disorders.

Implications:

• This research refines the understanding of the molecular mechanisms underlying PACS1-NDD.
• It highlights the importance of exploring other PACS1 variants beyond Arg203 for diagnosing intellectual disability.
• The findings may guide future diagnostic strategies and therapeutic interventions for related disorders.