Novel Compound Heterozygous CYBA Mutations Causing Neonatal-Onset

Abstract Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI) characterized by a defective respiratory burst by phagocytes and defective clearance of phagocytosed microorganisms; these phenomena, caused by a defect in NADPH oxidase, result in severe and life-threatening infections in affected children. The genetically heterogeneous X-linked recessive (XL-CGD) form of GCD is caused by mutations in the CYBB gene, whereas the autosomal recessive (AR-CGD) form is caused by mutations in the CYBA, NCF1, NCF2, NCF4, or CYBC1 genes. Mutations in the CYBA gene account for a small number of CGD cases; the vast majority of these patients become symptomatic in childhood, but rarely within the first weeks of life. Here, we report a 19-day-old neonate who developed pustular rashes and invasive pulmonary aspergillosis, which was identified by a galactomannan (GM) assay of both bronchoalveolar lavage fluid (BALF) and peripheral blood samples, and by metagenomic next-generation sequencing (mNGS) of BALF. A diagnosis of CGD was based on the respiratory burst test. Detailed assessment of neutrophil activity revealed that production of reactive oxygen species (ROS) was entirely absent. Whole-exome sequencing (WES) detected a nonsense mutation (c.7G>T). In addition, copy number variation (CNV) analysis detected a novel de novomicrodeletion of 200 kb at 16q24.2-q24.3. Thus, we have identified novel compound heterozygous CYBA mutations that cause neonatal AR-CGD, thereby expanding the clinical spectrum of CYBA deficiency.