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Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID
Federica Barbati1, Lorenzo Lodi2,3, Silvia Boscia3
1Pediatrics and Neonatology Unit, Santo Stefano Hospital, USL Toscana Centro, Prato, Italy.
Insights
Common variable immunodeficiency (CVID) is heterogeneous. This study identified genetic causes in 47% of pediatric CVID patients and developed a score to guide genetic testing for better diagnosis and treatment.
Area of Science:
- Immunology
- Genetics
- Pediatrics
Background:
- Common variable immunodeficiency (CVID) presents heterogeneous clinical and immunological features, complicating diagnosis.
- Understanding the genetic underpinnings of CVID is crucial for accurate patient stratification and management.
Purpose of the Study:
- To characterize a pediatric cohort of CVID patients clinically, immunologically, and genetically.
- To propose a model for prioritizing genetic investigations in pediatric CVID.
Main Methods:
- Whole exome sequencing was performed on 34 pediatric CVID patients.
- Clinical, immunological, and genetic data were analyzed to identify correlations with monogenic causes.
- A scoring system (Mo-CVID score) was developed based on key clinical and immunological criteria.
Main Results:
- Genetic variants were identified in 16 patients (47%), including known and novel mutations.
- Early onset, family history, autoimmunity, lymphoproliferation, and specific immune alterations were associated with a higher likelihood of a monogenic cause.
- The Mo-CVID score demonstrated potential in predicting the likelihood of a genetic mutation in pediatric CVID.
Conclusions:
- Genetic analysis is vital for understanding CVID heterogeneity and improving patient outcomes.
- The Mo-CVID score can assist clinicians in prioritizing genetic testing for pediatric CVID patients.
- Personalized treatment and genetic counseling can be enhanced through genetic stratification of CVID patients.
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.
