Genetic cause. Two patients are shown with their respective genetic mutations in the HYOU1 gene. Patient 1 has a homozygous mutation p.Pro444His, and Patient 2 has compound heterozygous mutations p.Arg262Gln and p.Pro757_Glu758insAla. The HYOU1 gene, mRNA, and protein are depicted, showing marked reduction in HYOU1 protein. Impaired ER-stress adaptation. Normal HYOU1 promotes protein folding and ER homeostasis, while HYOU1 deficiency leads to the accumulation of unfolded/misfolded proteins. Blunted UPR signaling is shown with PERK, IRE1, and ATF6 pathways. Fibroblasts treated with tunicamycin show blunted induction of ER-stress responsive genes, leading to ER proteostasis failure. Immune consequence. Adaptive immunity shows B-cell development arrest, with near-absence of circulating B cells and hypogammaglobulinemia. Innate immunity shows neutrophil dysfunction, with hypogranulated patient neutrophils and persistent hypogranulation. Combined disruption of adaptive and innate immunity leads to recurrent infections, immunodeficiency, neutropenia, and hypogammaglobulinemia.