Genetics of B Cell Maturation in Common Variable Immunodeficiency in Brazil: A Joint Analysis of the CVID-Brazil Cohort and the CNE3I Program

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency and remains underdiagnosed in Brazil due to limited knowledge of its genetic landscape. Since 2024, the Centro Nacional dos Erros Inatos da Imunidade e Imunodesregulação (CNE3i) has led the first nationwide initiative to systematically collect clinical, immunological, and genomic data on Brazilian patients with CVID. A total of 30 patients underwent genetic reanalysis; 53% were female (n = 16) and 47% male (n = 14), with a median age at diagnosis of 44 years. Most patients originated from the Southeast region, predominantly São Paulo (n = 24). Genetic variants in genes related to B cell development and function were identified in 15 patients, while no relevant variants were detected in the remaining 15 individuals. The majority of identified variants were classified as variants of uncertain significance (VUS), underscoring the complexity of genetic interpretation in CVID. Only one patient carried a clearly pathogenic variant in a well-established CVID-associated gene, NFKB1. In addition, CFTR variants were detected in four patients, including one heterozygous pathogenic variant (c.3154T>G, p.Phe1052Val), one likely pathogenic variant (c.1210-11T>G), and two heterozygous VUS (c.489+3A>G), suggesting a potential modifying contribution to disease expression rather than a primary monogenic cause. In conclusion, this first-year analysis highlights the marked genetic heterogeneity of CVID in a Brazilian cohort and reveals a high proportion of inconclusive variants, reflecting the limited representation of admixed populations in current genomic reference databases. These findings emphasize the critical need for continued genomic reanalysis, expansion of ancestry-diverse datasets, and careful genotype–phenotype correlation to improve diagnostic accuracy and advance precision medicine approaches for CVID in underrepresented populations.Tabular data are included as downloadable supplement files.