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PURPOSE: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients. METHODS: Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls. RESULTS: Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis. CONCLUSION: These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

Original publication




Journal article


J Clin Immunol

Publication Date





1315 - 1330


Apoptosis, CVID, DNA damage and repair, common variable immunodeficiency disorders, primary antibody deficiency, Adult, Aged, Aged, 80 and over, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Case-Control Studies, Common Variable Immunodeficiency, DNA Damage, DNA Repair, Female, Gene Expression, Humans, Male, Middle Aged, Phenotype, Young Adult