Genetic Diagnosis of Common Variable Immunodeficiency using Whole-exome Sequencing

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID) in adulthood. CVID is clinically and genetically heterogeneous. Patients have an increased susceptibility to infections, as well as autoimmunity, autoinflammation, lymphoproliferation, atopy, and cancer. In the last decades, Next Generation Sequencing (NGS) revolutionized the field of genetics. In the current 2018 IUIS classification, the number of molecularly defined immunodeficiency syndromes exceeded 450. Whole exome sequencing (WES) is widely considered an efficient and cost-effective approach to patients with PIDs. This study aimed to recruit a cohort of CVID patients and characterize them clinically, immunologically, and genetically. Using WES, we identified candidate variants in 50% of patients, including common disease-associated variants in TACI and BAFF-R genes, and novel variants in CTLA-4, CARD11, NFKB1, NFKB2, CD40LG, PIK3CD, PTEN, and TCF3. An unbiased approach like WES allows for unexpected discoveries. A pathogenic variant of CD40LG was found in a patient diagnosed with CVID. We also showed that in silico Copy Number Variants (CNV) prediction from NGS data can improve the diagnostic yield of WES. In a patient we found a deletion encompassing CD28, CTLA-4, and ICOS, leading to CTLA-4 haploinsufficiency. The discovery of the genetic defects of PID diseases contributed to our understanding of the immune system. Moreover, dissecting the underlying molecular mechanisms of CVID can improve clinical management. A genetic diagnosis can give relevant prognostic information, help tailor targeted therapies and it can inform about the heritability of the disease.