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.

Interpretable Inflammation Landscape of Circulating Immune cells

“…Mutations in CYBA cause an autosomal recessive chronic granulomatous disease and patients show an impaired phagocyte activation and fail to generate superoxide. Consequently, patients show recurrent bacterial and fungal infections in barrier tissues, including the skin 47 . Thus, we hypothesize that reduction of CYBA in skin-related IMIDs leads to an impaired immune barrier function and frequent recurrent infections causing localized, symptomatic flares of PS and PSA.…”