Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI) characterized by severe and recurrent infections resulting from defects in the NADPH oxidase complex, which impairs neutrophil function. Mutations in NCF2, which encodes the cytosolic component p67-phox, lead to autosomal recessive (AR) CGD. We describe a novel NCF2 variant identified in two unrelated patients with a clinical phenotype consistent with CGD.
As part of a national project to strengthen IEI diagnosis in Paraguay (2022–2024), we evaluated 115 children with recurrent infections. Forty-two patients with suggestive immunological findings underwent whole exome sequencing, supported by the Jeffrey Modell Foundation. In 17 cases, known pathogenic variants associated with IEI were identified. Additionally, a novel variant associated with AR-CGD was detected and confirmed by Sanger sequencing. Functional evaluation included in silico prediction tools and the dihydrorhodamine (DHR) assay.
The patients—a 6-year-old girl and an 8-year-old boy—were born to non-consanguineous, unrelated parents. Both presented with recurrent pneumonia and lymphadenitis; the boy had prior pulmonary tuberculosis and the girl developed pulmonary sepsis and digital necrosis requiring amputation. Both were homozygous for the NCF2 NM_000433.4:c.338G>A (p.Gly113Glu) variant. Their parents were heterozygous carriers. Although classified as a variant of uncertain significance (VUS) per American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, in silico analyses predicted high pathogenicity. Routine immunological workups were normal; however, both patients had abnormal DHR test results (stimulation index 60).
Clinical, genetic, and functional evidence supports the diagnosis of AR-CGD caused by this novel NCF2 variant. This finding expands the mutational spectrum of the NCF2 gene and underscores the importance of genetic analysis in diagnosing IEIs.
