W174 - Enhancer Hijacking of IgH Locus Leading to Antibody Deficiency and Invasive Streptococcus Pneumoniae Infection

Abstract Text: We investigated two families with an autosomal dominant pattern of invasive Streptococcus pneumoniae infection associated with specific antibody deficiency (SAD). In Family A, two male siblings presented at < 5 years with S. pneumoniae sepsis. The father had a history of meningitis and recurrent pneumonias, and a female sibling had milder infections. In Family B, a male presented during infancy with S. pneumoniae meningitis. All 5 individuals had significantly reduced memory B cells, and tested patients had normal serum immunoglobulin levels but poor responses to S. pneumoniae vaccination or infection. Primary B cells from patients had normal BCR spectratyping but diminished in vitro plasmablast differentiation. Whole genome sequencing identified similar ~650kb tandem duplications on Chr14q32.2 in all 5 individuals, encompassing part of the IGH locus and upstream genes, with complete penetrance in affected individuals. Bulk and scRNA-seq revealed B-cell-specific overexpression (100-fold) of one duplicated gene, JAG2, encoding the Notch ligand jagged-2. Long-read sequencing and Hi-C demonstrated the IGH locus interacting with JAG2 due to the duplication, supporting enhancer hijacking leading to overexpression of JAG2. Enhancer hijacking is well-described in cancer but has never been described in IEI. Overexpression of human JAG2 led to a defect in marginal zone B cell development in a bone marrow chimera. Together, these findings demonstrate a novel genetic mechanism of IEI, a new role for JAG2 in B cell differentiation, and a genetic cause of SAD. Ongoing work is focused on the effects of JAG2 overexpression on B cell function and an in vivo vaccination model.