Project Summary/Abstract Inborn errors of immunity (IEI) are genetic disorders of the immune system that can present with a wide diversity of signs and symptoms. Specific antibody deficiency (SAD) is among the most common classes of IEI and occurs when patients have normal levels of serum immunoglobulins but are unable to form specific responses to antigens. Despite its high prevalence, the pathogenesis of SAD remains poorly understood. Here, we investigate a family that presented with a specific antibody deficiency with an autosomal dominant inheritance pattern. Although whole exome sequencing did not reveal any variants in known IEI-associated genes, whole genome sequencing uncovered a heterozygous tandem duplication on chromosome 14 that intersects the immunoglobulin heavy chain (IgH) locus. All affected individuals also had a selective memory (CD27+ CD38 Lo/Int) B cell deficiency in peripheral blood. CD27- B cells were hyperproliferative in response to T-dependent and T-independent stimuli yet showed diminished differentiation to plasmablasts when stimulated with CD40L and IL-21. Intriguingly, one of the duplicated genes, JAG2 was upregulated more than 100-fold at baseline when measured by bulk RNA-seq. CITE-seq revealed that JAG2 is uniquely overexpressed in patient B cells but not in other immune cells. Given the diminished differentiation and B-cell-specific overexpression of JAG2 seen in these patients, we hypothesize that the duplication has transposed JAG2 under the transcriptional control of the IgH locus, a phenomenon known as ‘enhancer hijacking’, resulting in its increased expression only in B cells. We further hypothesize that the sustained expression of JAG2 upon stimulation results in diminished differentiation, leading to the clinical phenotype of SAD. Throughout this project, we will investigate the effects of JAG2 on B cell differentiation and explore the genetic mechanism of JAG2 overexpression using a number of cutting-edge techniques and novel models, including tonsil organoids and measles-pseudotyped lentivirus to manipulate the expression of JAG2 in human B cells and assess its effects on B cell differentiation. Previous studies of IEI have primarily focused on single nucleotide variants causing altered protein function or abundance. Here, we propose a structural variant is causing altered enhancer interactions between JAG2 and the IgH locus, resulting in SAD. This represents a novel genetic mechanism of IEI and would alter the way we approach the genetic diagnosis of IEI.