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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Germline variants were identified following targeted sequencing of <jats:italic>n<\/jats:italic>\u2009=\u2009252 genes related to DNA repair in <jats:italic>n<\/jats:italic>\u2009=\u200938 patients. NanoString nCounter PlexSet assay measured gene expression in <jats:italic>n<\/jats:italic>\u2009=\u200920 CVID patients and <jats:italic>n<\/jats:italic>\u2009=\u20097 controls. DNA damage and apoptosis were assessed by flow cytometry in <jats:italic>n<\/jats:italic>\u2009=\u200934 CVID patients and <jats:italic>n<\/jats:italic>\u2009=\u200911 controls.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10875-021-01050-2","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T15:21:03Z","timestamp":1621437663000},"page":"1315-1330","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders"],"prefix":"10.1007","volume":"41","author":[{"given":"Chantal E.","family":"Hargreaves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Salatino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah C.","family":"Sasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E. 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