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

Matthew Du – Washington University School of Medicine; Changxu Fan – Washington University School of Medicine; Tony Yao – Washington University School of Medicine; Birk Evavold – Washington University School of Medicine; Alex Paul – Washington University School of Medicine; Ana Kolicheski – Washington University School of Medicine; Jennifer Poursine-Laurent – Washington University School of Medicine; Nermina Saucier – Washington University School of Medicine; Rachel Bielecki – Washington University School of Medicine; Yongjun Wang – Washington University School of Medicine; Kristen McDaniels – Washington University School of Medicine; Tomoki Kawai – National Institute of Allergy and Infectious Diseases; David LaFon – Division of Pulmonary, Allergy, and Critical Care Medicine – University of Alabama at Birmingham; John Kuster – Pediatrics – Yale University School of Medicine; Peggy Kendall – Division of Allergy and Immunology – Washington University School of Medicine; Caroline Horner – Pediatrics – Washington University School of Medicine; Naresha Saligrama – Pathology and Immunology – Washington University School of Medicine; Luigi Notarangelo – National Institute of Allergy and Infectious Diseases; Richard James – Seattle Children's Hospital; Stuart Tangye – Garvan Institute of Medical Research; Ting Wang – Washington University School of Medicine; Jeffrey Bednarski – Washington University School of Medicine; Neil Romberg – Children's Hospital of Philadelphia; Ali Ellebedy – Washington University School of Medicine; Megan Cooper – Washington University School of Medicine

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.