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Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

Original publication




Journal article


Clin Immunol

Publication Date





301 - 314


B-cell, Common variable immunodeficiency, Polygenic, Transcriptome, Whole genome sequencing, Adaptor Proteins, Signal Transducing, Adolescent, Adult, B-Cell Activation Factor Receptor, B-Lymphocytes, Case-Control Studies, Child, Child, Preschool, Common Variable Immunodeficiency, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Multifactorial Inheritance, RNA, Messenger, Sequence Analysis, DNA, Sequence Analysis, RNA, Transmembrane Activator and CAML Interactor Protein, Young Adult