Common variable immunodeficiency, same name but different etiologies: unraveling heterogeneity through functional and genetic profiling
12 affiliations
- 1Department of Immunology, Hospital Universitario 12 de Octubre
- 2Instituto de Investigación Sanitaria Hospital 12 Octubre (imas12)
- 3School of Medicine, Complutense University of Madrid
- 4Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH
- 5Department of Internal Medicine, Hospital Universitario Galdakao-Usansolo
- 6Biobizkaia Health Research Institute (IIS Biobizkaia)
- 7Interdepartmental Group of Immunodeficiencies
- 8Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital
- 9CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III
- 10Department of Immunology, Hospital Universitario La Paz
- 11Department of Immunology, Centre Diagnostic Biomedic, Hospital Clinic de Barcelona
- 12Department of Immunology, Fundación Jiménez Díaz
Abstract
Introduction: Common variable immunodeficiency (CVID) represents a challenge for medical genomics, as it does not fully conform to a classical Mendelian inheritance model. Beyond the monogenic model, diverse molecular mechanisms, including polygenic contributions, somatic mutations, epigenetic modifications, and skewed X-chromosome inactivation, may play relevant roles in disease development, driving a broad clinical spectrum from classical antibody deficiency to complex immune dysregulation. Integrating clinical, immunological, functional, and genetic data is therefore essential to unravel this complexity and advance toward personalized precision medicine.
Methods: We conducted an in-depth clinical, immunological, functional, and genetic characterization of four distinct selected cases (P1–P4) from a cohort of adult patients with CVID. Targeted next-generation sequencing (NGS), cytokine profiling, and specific in vitro functional assays were performed to validate B-cell maturation defects, intracellular signaling, and variant pathogenicity.
Results: We identified novel and rare pathogenic variants in key B-cell pathways that converged on a common B-cell maturation defect but diverged into distinct phenotypes. Patient 1 (P1) presented a novel IKZF1 variant that disrupted early B-cell ontogeny, whereas Patient 2 (P2) exhibited a rare compound heterozygous defect in TNFRSF13B (TACI) that affected peripheral B-cell activation, both manifesting a predominantly infectious phenotype. In contrast, Patients 3 and 4 presented with severe immune dysregulation. Patient 3 (P3) harbored a novel splice-site deficiency in LRBA , while Patient 4 (P4) exhibited concurrent heterozygous variants in BLK and EBF1 , supporting a novel oligogenic "double-hit" hypothesis. Functional assays validated the deleterious impact of these variants across all cases.
Discussion: Our findings not only expand the known phenotypic spectrum but also underscore the value of functional assays in validating novel genotypes. Ultimately, this comprehensive profiling provides essential insights to refine prognosis and advance toward tailored precision medicine in CVID.
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BibTeX
@article{nietolopez2026common,
title = {{Common variable immunodeficiency, same name but different etiologies: unraveling heterogeneity through functional and genetic profiling}},
author = {Celia Nieto-López and Lucía Dueñas-Prieto and Hye Sun Kuehn and Juan D. Acevedo-Ávila and Luis A. Andara and María J. Díaz-Madroñero and Kima López-Aldabe and Juan José Fernández-Díaz and Estela Paz-Artal and Rebeca Pérez de Diego and Rebeca Rodríguez-Pena and Mario Framil and Sergio D. Rosenzweig and Oscar Cabrera-Marante and Cristina Serrano and Luis M. Allende},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1918470},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918470/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Common variable immunodeficiency, same name but different etiologies: unraveling heterogeneity through functional and genetic profiling
AU - Celia Nieto-López
AU - Lucía Dueñas-Prieto
AU - Hye Sun Kuehn
AU - Juan D. Acevedo-Ávila
AU - Luis A. Andara
AU - María J. Díaz-Madroñero
AU - Kima López-Aldabe
AU - Juan José Fernández-Díaz
AU - Estela Paz-Artal
AU - Rebeca Pérez de Diego
AU - Rebeca Rodríguez-Pena
AU - Mario Framil
AU - Sergio D. Rosenzweig
AU - Oscar Cabrera-Marante
AU - Cristina Serrano
AU - Luis M. Allende
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1918470
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1918470/full
AB - Introduction: Common variable immunodeficiency (CVID) represents a challenge for medical genomics, as it does not fully conform to a classical Mendelian inheritance model. Beyond the monogenic model, diverse molecular mechanisms, including polygenic contributions, somatic mutations, epigenetic modifications, and skewed X-chromosome inactivation, may play relevant roles in disease development, driving a broad clinical spectrum from classical antibody deficiency to complex immune dysregulation. Integrating clinical, immunological, functional, and genetic data is therefore essential to unravel this complexity and advance toward personalized precision medicine. Methods: We conducted an in-depth clinical, immunological, functional, and genetic characterization of four distinct selected cases (P1–P4) from a cohort of adult patients with CVID. Targeted next-generation sequencing (NGS), cytokine profiling, and specific in vitro functional assays were performed to validate B-cell maturation defects, intracellular signaling, and variant pathogenicity. Results: We identified novel and rare pathogenic variants in key B-cell pathways that converged on a common B-cell maturation defect but diverged into distinct phenotypes. Patient 1 (P1) presented a novel IKZF1 variant that disrupted early B-cell ontogeny, whereas Patient 2 (P2) exhibited a rare compound heterozygous defect in TNFRSF13B (TACI) that affected peripheral B-cell activation, both manifesting a predominantly infectious phenotype. In contrast, Patients 3 and 4 presented with severe immune dysregulation. Patient 3 (P3) harbored a novel splice-site deficiency in LRBA , while Patient 4 (P4) exhibited concurrent heterozygous variants in BLK and EBF1 , supporting a novel oligogenic "double-hit" hypothesis. Functional assays validated the deleterious impact of these variants across all cases. Discussion: Our findings not only expand the known phenotypic spectrum but also underscore the value of functional assays in validating novel genotypes. Ultimately, this comprehensive profiling provides essential insights to refine prognosis and advance toward tailored precision medicine in CVID.
SN - 1664-3224
ER -