Five CGD-Linked CYBB Mutations in Chinese Patients: Insights Into Predicting IFN-γ Treatment Efficacy

Background The CYBB gene encodes the gp91-phox protein, a critical component of the NADPH oxidase complex involved in pathogen clearance. Mutations in CYBB are associated with chronic granulomatous disease (CGD), leading to recurrent bacterial infections. Objective To understand the genetic causes of Chinese CGD patients. Methods Exome sequencing was used to identify mutations in CGD patients' PBMCs, confirmed by Sanger sequencing. Neutrophil respiratory burst capacity was analyzed to correlate with clinical treatment efficacy. Results We identified five CYBB mutations in six CGD patients from five unrelated Chinese families, including two novel mutations (c.1507A > G:p.T503A, c.1587_1605del:p.529_535del), two rare mutations without functional characterization (c.43A > G:p.I15V, c.125C > A:p.T42K), and one recently reported in a different ethnicity (c.252G > T:p.A84A). Our analysis revealed that these mutations had varying effects on CYBB expression, demonstrating that the synonymous c.252G > T mutation is indeed a splicing mutation, resulting in exon 3 deletion and minimal protein expression. Neutrophils from all patients exhibited defective mitogen-stimulated respiratory bursts. However, only neutrophils with the I15V mutation responded to interferon-γ (IFN-γ) treatment, significantly improving the respiratory capacity defect. Consistent with this, the patient with the I15V mutation showed clinical improvement after two weeks of IFN-γ and anti-bacterial co-treatment. Conclusion Our findings underscore the diverse effects of CYBB mutations on protein expression and function. More importantly, they suggest that assessing the IFN-γ-mediated potentiation of respiratory burst response in patient's neutrophils is an effective way to predict the therapeutic efficacy of IFN-γ in treating CGD cases, particularly those with non-tuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (TB).