Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency

TRAF3, a versatile adaptor protein within the TRAF family, participates in various signaling pathways involving the tumor necrosis factor receptor, toll-like receptor, and retinoic acid-inducible gene I-like receptor families. In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production. Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3^Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia. In this study, we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity. Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3^Hl within two different families. These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia. Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy. In addition, a TRAF3 start-loss variant (c.3G > A) was identified in a fourth patient, but after familial and molecular studies, it was not considered disease-causing, excluding TRAF3^Hl in this patient. This study illustrates the usefulness of targeted reanalysis of genes with reported novel phenotypes. We rescued three patients with TRAF3^Hl, presenting similarities and differences with the previously reported patients. The most significant differences were hypogammaglobulinemia and a CVID-like presentation. These data expand the clinical phenotype of TRAF3^Hl and pave the way for further investigation into loss-of-function variants in patients with CVID.