Abstract
Purpose
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, representing an "umbrella" diagnosis due to its clinical and immunological heterogeneity. The primary objective of this study was to describe a cohort of pediatric subjects with CVID, characterizing them from clinical, immunological, and genetic viewpoints. Secondary, we propose a model for prioritizing genetic investigations in these patients.
Methods
Patients with a CVID diagnosis followed at Meyer Children’s Hospital, IRCSS, Florence, were enrolled. Whole exome sequencing (WES) was performed according to the latest update of the International Union of Immunological Societies 2022.
Results
Thirty-two patients were enrolled. Genetic variants were identified in 17 patients (53%), including known variants in SLC39A7, PRKCD, STAT3, NFKB1, PIK3R1, PLCG2, RFXANK, PRKDC, TNFRSF13B, and novel variants in SPI1 and NFKB1. Comparing the gene-positive and gene-negative patients cohorts, we demonstrated that a CVID monogenic cause is more likely to be found in case of early disease onset, positive family history, autoimmunity, lymphoproliferation, and specific immunological alterations. Using these criteria, we developed a pediatric Monogenic CVID (Mo-CVID) scoring system to hypothesize when a pediatric patient is more likely to have a genetic mutation causing CVID.
Conclusion
Genetic analysis in CVID patients can help stratifying patients into different disease entities to predict complications and prognosis, ensure appropriate genetic counseling and possibly personalize treatment. A scoring system such as Mo-CVID score could help physicians to prioritize genetic testing, and to perform further genetic testing in patients with high score but with negative first analysis.