Monogenic Common Variable Immunodeficiency (Mo‐CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort

• Published in: European journal of immunology Vol. 55; no. 3; pp. e202451433 - n/a
• Main Authors: Barbati, Federica, Lodi, Lorenzo, Boscia, Silvia, Cortimiglia, Martina, Calistri, Elisa, Quaranta, Francesca, Maggi, Laura, Mazzoni, Alessio, Palterer, Boaz, Annunziato, Francesco, Azzari, Chiara, Ricci, Silvia
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.03.2025; John Wiley and Sons Inc
• Subjects: Adolescent; Autoimmune diseases; Autoimmunity; Child; Child, Preschool; children; Cohort Studies; Common variable immunodeficiency; Common Variable Immunodeficiency - diagnosis; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Diagnosis; Exome Sequencing; Female; Genetic analysis; Genetic counseling; Genetic diversity; Genetic Predisposition to Disease; Genetic screening; Genetic Testing - methods; Humans; Immune system; Immunodeficiencies and Autoimmunity; Immunology; Male; Mutation; Patients; Pediatrics; primary immunodeficiency; prioritization; Stat3 protein; Whole genome sequencing; primary immunodeficiency; exome sequencing; common variable immunodeficiency; children; prioritization
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202451433

ABSTRACT Common variable immunodeficiency (CVID) represents an “umbrella” diagnosis due to its clinical and immunological heterogeneity. The primary objective of this study was to describe a cohort of CVID pediatric subjects from clinical, immunological, and genetic viewpoints. Secondary, we propose a model for prioritizing genetic investigations in these patients. Thirty‐four patients with CVID followed at Meyer Children's Hospital, IRCSS, were enrolled. Whole exome sequencing was performed according to the latest International Union of Immunological Societies 2022 update. Genetic variants were identified in 16 patients (47%), including known variants in SLC39A7, PRKCD, STAT3, NFKB1, PIK3R1, PLCG2, RFXANK, PRKDC, TNFRSF13B, and novel variants in SPI1, NFKB1, NFKB2. Comparing the Gene+ and Gene− cohorts, we demonstrated that a monogenic cause is more likely to be found in cases of early disease onset, positive family history, autoimmunity, lymphoproliferation, and specific immunological alterations. Using these criteria, we developed a pediatric monogenic CVID (Mo‐CVID) score to hypothesize when a CVID pediatric patient is more likely to carry a genetic mutation. A scoring system such as the Mo‐CVID score could help physicians prioritize genetic testing. Genetic analysis in CVID patients can help stratify patients into different disease entities to predict complications and prognosis, ensure appropriate genetic counseling, and personalize treatment. A mutation was identified in 47% of the CVID‐enrolled patients and, in the majority, it was not related to CVID according to the IUIS classification, leading to a diagnostic metamorphosis of this pathological entity. The Mo‐CVID Score could help clinicians prioritize genetic analysis in pediatric CVID patients. The image was created with BioRender.com.