Abstract
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.
Highlights
Common Variable Immunodeficiency Disorders (CVIDs) are the most clinically prevalent primary antibody deficiencies, present in about 1 in 25,000 people [1]
Causative variants of CVID-like primary antibody failure have been described in CD19 [4,5,6], CD21 [7], CD81 [8], CD20 [9], ICOS [10,11] and TNFRSF13C [12], conditions classified as specific deficiencies in these genes (Table S1)
In our analysis strategy (Fig. 1c) we focused on variants present in regions implicated in genome-wide association study (GWAS) [30], genes involved in described primary immunodeficiency disorders (PIDs) or genes with a direct link with previously identified CVID genes
Summary
Common Variable Immunodeficiency Disorders (CVIDs) are the most clinically prevalent primary antibody deficiencies, present in about 1 in 25,000 people [1]. Causative variants of CVID-like primary antibody failure have been described in CD19 [4,5,6], CD21 [7], CD81 [8], CD20 [9], ICOS [10,11] and TNFRSF13C [12], conditions classified as specific deficiencies in these genes (Table S1). Variants in TNFRSF13B [24,25,26], TNFRSF13C [27], FCGR2A [28] and HLA [29] have been described to predispose to CVID (Table S1) Together these variants only explain the genetic cause of CVID-like diseases in very few patients and all genes were identified in familial cases of CVID, while the vast majority of CVID patients are sporadic. Further unravelling of the underlying genetic causes of sporadic CVID would give additional insight into the disease, opportunities for better patient stratification and novel insights into treatment opportunities
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