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Clin Immunol. 2015 Oct;160(2):301-14. doi: 10.1016/j.clim.2015.05.020. Epub 2015 Jun 26.

Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders.

Author information

1
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
2
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
3
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
4
Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
6
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Centre for Computational Biology, University of Birmingham, Haworth Building, B15 2TT Edgbaston, UK.
7
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: julian@well.ox.ac.uk.
8
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. Electronic address: smita.patel@ndm.ox.ac.uk.

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.

KEYWORDS:

B-cell; Common variable immunodeficiency; Polygenic; Transcriptome; Whole genome sequencing

PMID:
26122175
PMCID:
PMC4601528
DOI:
10.1016/j.clim.2015.05.020
[Indexed for MEDLINE]
Free PMC Article

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