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).