We investigated the genetic cause of disease in five affected individuals from two unrelated families with an autosomal dominant pattern of invasive Streptococcus pneumoniae infection associated with a clinical phenotype of specific antibody deficiency. In Family A, two male siblings presented at <5 years with sepsis due to S. pneumoniae. The father had a history of meningitis and recurrent pneumonias, and a female sibling had less severe infections. In Family B, a male presented during infancy with S. pneumoniae meningitis with no family history of immunodeficiency. All patients had significantly decreased switched (CD27+IgD-) and unswitched (CD27+IgD+) memory B cells with normal serum immunoglobulin (Ig) levels, but poor responses to the polysaccharide pneumococcal vaccine or the serotype of S. pneumoniae causing infection. Primary B cells from patients had normal BCR spectratyping. Despite a hyperproliferative phenotype, plasmablast differentiation was diminished in vitro. Whole-genome sequencing identified similar ∼650-kb tandem duplication events on Chr14q32.2 encompassing part of the IGH locus and upstream genes, with complete penetrance in all patients from both families. Bulk and scRNA-seq revealed B cell–specific massive overexpression (100-fold) of one gene within the duplication, JAG2, encoding the Notch ligand jagged-2. Primary B cells and patient-derived B-LCLs expressed high JAG2 protein. Long-read sequencing demonstrated the 3’ regulatory region (3’RR) of the IGH locus in close proximity to JAG2 due to the duplication, and we hypothesize this leads to enhancer hijacking and dysregulation of JAG2 in B cells. Enhancer hijacking is a well-described mechanism leading to cancer but has never been described in IEI and very rarely in Mendelian genetics. Consistently, Hi-C analysis of patient-derived B-LCLs demonstrated a new interaction of JAG2 with the IGH 3’RR. A bone marrow chimera model demonstrated that overexpression of human JAG2 leads to a defect in marginal zone B cell development. Together, these findings demonstrate the discovery of a novel genetic mechanism of IEI, a new role for JAG2 in B cell differentiation, and a genetic cause of specific antibody deficiency. Ongoing work is focused on the effects of JAG2 overexpression on B cell function in vitro and using an in vivo model of vaccination.
