Abnormalities in V(D)J recombination in common variable immunodeficiency disorders

The common variable immunodeficiency disorders (CVIDs) comprise a group of heterogeneous primary antibody deficiencies and form the most clinically significant antibody failure in adults and children. For the majority of patients with CVIDs the condition is sporadic, heterogeneous and polygenic.

We have applied whole genome sequencing techniques to a small cohort of patients with sporadic CVID and preliminary findings reveal multiple variants in the DNA repair pathway, in particular the V(D)J recombination associated genes. We will use next generation sequencing techniques to identify V(D)J recombination defects on CVID patients and establish a causative link by mimicking identified defects in fibroblast cell lines using the CRISPR-Cas9 system. We will study the functional effect by analysing expression and radiosensitivity using the gH2AX assay. We will then link the genetic and functional defects back to the clinical phenotype.

We expect to identify a subgroup of patients with CVID with defects in V(D)J recombination that explains their complex phenotype. This will lead to better stratification, earlier diagnosis and potential new treatments targeting the DNA repair pathway.