Novel genetic associations with common variable immunodeficiency

Abstract: Common variable immunodeficiency (CVID) is the most frequently encountered primary immunodeficiency disorder in clinical practice and is a cause of significant morbidity and mortality for patients. The main clinical features are hypogammaglobulinemia, recurrent infections and autoimmune disorders. Unlike the majority of primary immunodeficiency disorders, pinpointing a specific genetic association has been challenging. The objective of this work was to use next generation sequencing (NGS) technology in the form of whole exome sequencing (WES) to identify genetic associations with CVID. Candidate patients were selected based on parental consanguinity and availability of clinical specimens from them and their family members. Whole exome sequencing was performed and identified potential mutations which were confirmed by Sanger sequencing, followed by characterization of the novel mutations by immunological techniques. In Paper I, genetic analysis identified four novel CD27 mutations: homozygous missense mutations C96Y and R78W; heterozygous nonsense C10X; and compound heterozygous W8X-R107C resulting in a clinical phenotype of CD27 deficiency. In Paper II, whole exome sequencing revealed a novel W56X mutation in the RAC2 gene resulting in a CVID-like phenotype with prominent autoimmune disease. Newly identified abnormalities of neutrophil granules were identified by transmission electron microscopy. In Paper III, five novel mutations in the LRBA gene resulting in varied clinical phenotypes were presented in the context of a review of all published cases, thus providing a clinical summary. In conclusion, this work has shown the validity of employing whole exome sequencing in identifying genetic associations with CVID and CVID-like disease; and has provided a better overview of the diverse clinical phenotypes associated with mutations in CD27, RAC2 and LRBA and their resultant protein deficiencies.