Case Report: Severe neonatal-onset chronic granulomatous disease associated with biallelic copy-number loss encompassing NCF1

NCF1-related chronic granulomatous disease (CGD) is rarely recognized during the neonatal period, and large structural variants involving NCF1 are technically challenging to characterize because of the highly homologous neighboring pseudogenes. We report a male neonate who developed fever and progressive respiratory disease at 17 days of age and was subsequently diagnosed with invasive pulmonary Aspergillus fumigatus infection. Dihydrorhodamine flow cytometry demonstrated a markedly impaired but detectable PMA-induced oxidative-burst response. Whole-exome sequencing with copy-number analysis suggested a biallelic copy-number loss encompassing the NCF1 locus. Independent whole-genome sequencing showed markedly reduced sequencing coverage across NCF1 , while quantitative PCR targeting exons 2 and 6 and parental segregation analysis provided orthogonal support for the deletion. Despite intensive antimicrobial and antifungal treatment, the patient developed progressive respiratory failure and died at 2 months of age after withdrawal of life-sustaining treatment. An updated literature review identified 87 reported patients with neonatal-onset CGD, including only four with NCF1 deficiency. This case expands the clinical and structural-variant spectrum of NCF1-related CGD and highlights the value of integrating functional testing with copy-number-sensitive genomic approaches when evaluating technically challenging, pseudogene-rich loci.