Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience

Background:

• Forkhead box (FOX) proteins are crucial transcription factors.
• Mutations in FOXP1, FOXP2, and FOXG1 genes are linked to neurodevelopmental disorders (NDDs).
• Determining the pathogenicity of missense mutations in these genes is challenging due to a lack of site-specific statistical significance.

Observation:

• A novel de novo missense mutation (c.G1444A, p.E482K) in FOXP1 was identified in a patient with intellectual disability and severe speech delay.
• This mutation led to a significant reduction in both mRNA and protein expression, suggesting a loss-of-function mechanism.
• The majority of de novo or transmitted missense variants were located within FOX domains, with 95% classified as pathogenic.

Findings:

• Missense variants outside FOX domains were classified as likely pathogenic or of uncertain significance.
• The study establishes the pathogenicity of missense and inframeshift variants in NDD-related FOX genes.
• A significant portion of variants within FOX domains were confirmed as pathogenic.

Implications:

• This research is vital for improving the clinical diagnosis and genetic counseling of individuals with NDDs.
• Functional analysis is recommended to clarify the pathogenicity of variants with uncertain clinical significance.
• Understanding the impact of these genetic variants can guide future research into NDDs.