Chronic Granulomatous Disease via the NCF4 Gene

Chronic granulomatous disease (CGD) is an inherited immunodeficiency characterized by repeated infections with bacterial and fungal pathogens and formation of granulomas. CGD immunodeficiency is due to an impairment of the NADPH oxidase complex resulting in an inability to generate superoxide in phagocytic cells to lyse pathogens (Song et al. 2011). Common pathogens include Staphylococcus aureus, Pseudomonas species, Candida albicans, Aspergillus species, and Nocardia species. Pneumonia, granuloma formation within gastrointestinal and genitourinary tracts, and failure to thrive are hallmark symptoms of the disorder.

CGD via pathogenic variants in the NCF4 gene has only been reported in one case to date. The patient was a 3 year old boy with granulomatous colitis. Other symptoms included recurrent episodes of croup, eczema, sinusitis, non-hemorrhagic diarrhea, intermittent abdominal pain and a low grade fever (Matute et al. 2009).

CGD is primarily inherited in an X-linked manner through pathogenic variants in the CYBB gene. Autosomal recessive forms of CGD also occur through pathogenic variants in the CYBA, NCF1, NCF2, and NCF4 genes (Roos and de Boer 2014). To date, only two variants, c.143_152dup10 (p.Lys52Argfsx79) and c.314G>A (p.Arg105Gln) have been reported in the NCF4 gene in a compound heterozygous individual (Matute et al. 2009). The NCF4 gene encodes the p40 phox protein which is a subunit of the NAPDH oxidase enzyme. This complex is essential for the production of superoxide which is central for intracellular killing of pathogens in phagocytes (Song et al. 2011).

Clinical sensitivity cannot be estimated because only one patient has been reported to date. Analytical sensitivity may be high as all pathogenic variants in the NCF4 gene reported are detectable by sequencing.

This test provides full coverage of all coding exons of the NCF4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).