Impaired IFN-γ-mediated innate and adaptive immunity in Coffin-Siris syndrome type 2: immunological insights from a patient with a recurrent ARID1A mutation

Abstract

Background Coffin-Siris syndrome type 2 (CSS2), caused by ARID1A mutations, is characterized by neurodevelopmental delay and recurrent infections. The ARID1A p.Ala1077Glu variant has been linked to CSS2, but the immune mechanisms underlying infection susceptibility remain poorly understood. Methods The variant was identified by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Immune status was assessed via serum immunoglobulins, complement measurements, and flow cytometric immunophenotyping. RNA sequencing was performed on PMA-stimulated PBMCs from the patient and healthy controls, with key findings validated by qRT-PCR and ELISA. Results Immune profiling revealed widespread quantitative deficits across innate and adaptive compartments, with particularly marked reductions in NKT-like cells (CD3+CD56+) and CD8+ central memory T cells. Transcriptomic analysis of stimulated cells uncovered a profound activation defect, characterized by widespread downregulation of effector immune genes. Furthermore, pathway enrichment analysis demonstrated significant suppression of multiple biological processes critically dependent on IFN-γ signaling, such as antigen processing and presentation, and Th1/Th17 cell differentiation. Expression of IFNG, STAT1, and CXCL9 showed a trend toward decreased expression. Conclusion Our findings suggest an association between the ARID1A p.Ala1077Glu variant and impaired IFN-γ-mediated immunity in CSS2, potentially contributing to recurrent infections. The IFN-γ pathway warrants further investigation as a therapeutic target.