Impaired IFN-γ-mediated innate and adaptive immunity in Coffin-Siris syndrome type 2: immunological insights from a patient with a recurrent ARID1A mutation - Report - MDSpire
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Impaired IFN-γ-mediated innate and adaptive immunity in Coffin-Siris syndrome type 2: immunological insights from a patient with a recurrent ARID1A mutation
Clinical Report: Deficient IFN-γ-Driven Immune Responses in CSS Type 2
Background
Coffin-Siris syndrome type 2 (CSS2) is a rare neurodevelopmental disorder characterized by intellectual disability and recurrent infections, affecting approximately 60% of patients. The underlying immune dysfunction associated with CSS2, particularly related to ARID1A mutations, remains poorly understood.
Data Highlights
Immune profiling revealed widespread quantitative deficits across innate and adaptive compartments, particularly in NKT-like cells (CD3+CD56+) and CD8+ central memory T cells. Transcriptomic analysis indicated a significant downregulation of effector immune genes and suppression of biological processes reliant on IFN-γ signaling.
Key Findings
ARID1A p.Ala1077Glu variant linked to impaired IFN-γ-mediated immunity in CSS2.
Marked reductions in NKT-like cells (CD3+CD56+) and CD8+ central memory T cells observed.
Transcriptomic analysis showed widespread downregulation of effector immune genes.
Pathway enrichment analysis indicated significant suppression of processes dependent on IFN-γ signaling.
Expression of IFNG, STAT1, and CXCL9 showed a trend toward decreased expression.
Clinical Implications
The findings suggest that patients with CSS2 and the ARID1A p.Ala1077Glu variant may be at increased risk for recurrent infections due to impaired immune responses. Clinicians should consider monitoring immune function in these patients and explore potential therapeutic targets within the IFN-γ pathway.
Conclusion
This study highlights the association between ARID1A mutations and immune dysregulation in CSS2, emphasizing the need for further research into the IFN-γ signaling pathway as a potential therapeutic target.
