title: Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders.
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.
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: van Schouwenburg
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Davenport
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Kienzler
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Ishita
authors.initials: I
authors.lastname: Marwah
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wright
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Malinauskas
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Lockstone
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Centre for Computational Biology, University of Birmingham, Haworth Building, B15 2TT Edgbaston, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Chapel
authors.affiliation: 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.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: 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.
authors.forename: Smita Y
authors.initials: SY
authors.lastname: Patel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D053265:B-Cell Activation Factor Receptor / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016678:Genome / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D012333:RNA, Messenger / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053265:B-Cell Activation Factor Receptor; D047908:Intracellular Signaling Peptides and Proteins; C476731:NLRP12 protein, human; D012333:RNA, Messenger; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; C428703:LRBA protein, human
keywords: B-cell; Common variable immunodeficiency; Polygenic; Transcriptome; Whole genome sequencing