Expanding the clinical spectrum associated with PACS2 mutations

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Medicine

Background:

• Whole exome sequencing (WES) is crucial for understanding neurodevelopmental disorders, including intellectual disability (ID) and developmental and epileptic encephalopathies (DEEs).
• PACS2 mutations were recently identified as a cause of DEE, characterized by cerebellar dysgenesis and facial dysmorphism, typically associated with a recurrent c.625G>A (p.Glu209Lys) mutation.

Observation:

• A 7-year-old boy presented with DEE, cerebellar dysgenesis, facial dysmorphism, and postnatal growth delay, not fitting any established diagnosis.
• WES revealed a novel de novo PACS2 variant, c.631G>A (p.Glu211Lys), as the likely cause of his complex phenotype.

Findings:

• The study details the clinical presentation of this patient with the novel PACS2 variant.
• Analysis of available clinical data for individuals with PACS2 mutations refines the understanding of the associated neurodevelopmental syndrome.
• The key features of PACS2-related disorders include moderate to severe ID, cerebellar and other central nervous system malformations, growth reduction, and facial dysmorphism.

Implications:

• This research expands the known clinical and molecular spectrum of PACS2 mutations.
• It highlights the importance of WES in diagnosing complex neurodevelopmental disorders with novel genetic variants.
• The findings contribute to a more accurate delineation of PACS2-associated neurodevelopmental conditions, aiding future diagnostics and research.