Common variable immunodeficiencies (CVIDs) are the most frequent symptomatic primary immunodeficiencies, with an estimated frequency of 1:25,000. CVID type 2, linked to TNFRSF13B mutations (TACI), shows autosomal dominant or recessive inheritance, incomplete penetrance, and variable expressivity. The 2025 International Union of Immunological Societies update highlights its genetic complexity among 508 genes and 17 phenocopies.
We present a 14-year-old male with chronic lung disease, including bronchiectasis and obliterative bronchiolitis, recurrent otitis media, and severe respiratory infections. He required intensive care unit admission and lobectomy. He is currently treated with subcutaneous immunoglobulin, bronchodilators, and leukotriene receptor antagonists. Whole exome sequencing revealed a likely pathogenic heterozygous frameshift variant in TNFRSF13B (c.49del; p.(Gln17ArgfsTer15)), inherited from his asymptomatic mother. This supports a diagnosis of CVID type 2 and demonstrates incomplete penetrance. Family history includes a healthy sister and a grandmother with asthma.
This case highlights the importance of molecular diagnosis in CVID, particularly in patients with early-onset or atypical manifestations. A pathogenic TNFRSF13B variant (c.49del) was identified in both the patient and his asymptomatic mother, underscoring incomplete penetrance and phenotypic variability. This variant likely leads to a truncated, nonfunctional TACI receptor, impairing B cell signaling. Despite its classification as likely pathogenic by American College of Medical Genetics and Genomics criteria, expression may be modulated by genetic or epigenetic factors. These findings emphasize the need for long-term monitoring of carriers. Immunoglobulin therapy was effective, aligning with current CVID management recommendations.
The patient was diagnosed with CVID type 2 due to a likely pathogenic TNFRSF13B variant, also found in his asymptomatic mother. This highlights incomplete penetrance and phenotypic variability. Clinical and genetic correlation is essential for accurate diagnosis, long-term monitoring of carriers, personalized treatment, and appropriate genetic counseling within families.
