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

• Published in: Journal of clinical immunology 2025-12, Vol.45 (1), p.47-47, Article 47
• Main Authors: Urban, Blanca, Batlle-Masó, Laura, Perurena-Prieto, Janire, Garcia-Prat, Marina, Parra-Martínez, Alba, Aguiló-Cucurull, Aina, Martinez-Gallo, Mónica, Moushib, Laith, Antolín, María, Rivière, Jacques G., Soler-Palacin, Pere, Dieli-Crimi, Romina, Franco-Jarava, Clara, Colobran, Roger
• Format: Article
• Language: English
• Subjects: Adaptor proteins; Adult; Bacterial infections; Biomedical and Life Sciences; Biomedicine; Child; Common variable immunodeficiency; Common Variable Immunodeficiency - diagnosis; Common Variable Immunodeficiency - genetics; Encephalitis; family; Female; genes; Haploinsufficiency; Herpes simplex; heterozygosity; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Hypergammaglobulinemia; Hypogammaglobulinemia; Immune system; immunoglobulins; Immunology; immunosuppression; Infectious Diseases; inflammation; interferons; Internal Medicine; Loss of Function Mutation; Male; Medical Microbiology; Next-generation sequencing; Patients; Pedigree; Phenotype; Phenotypes; Retinoic acid; therapeutics; TNF Receptor-Associated Factor 3 - genetics; Toll-like receptors; tumor necrosis factor receptors
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01833-3

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.