TY - JOUR
T1 - Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders
AU - van Schouwenburg, Pauline A
AU - Davenport, Emma E
AU - Kienzler, Anne-Kathrin
AU - Marwah, Ishita
AU - Wright, Benjamin
AU - Lucas, Mary
AU - Malinauskas, Tomas
AU - Martin, Hilary C
AU - Lockstone, Helen E
AU - Cazier, Jean-Baptiste
AU - Chapel, Helen M
AU - Knight, Julian C
AU - Patel, Smita Y
AU - WGS500 Consortium
N1 - Copyright © 2015. Published by Elsevier Inc.
PY - 2015/10
Y1 - 2015/10
N2 - 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.
AB - 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.
UR - http://europepmc.org/abstract/med/26122175
U2 - 10.1016/j.clim.2015.05.020
DO - 10.1016/j.clim.2015.05.020
M3 - Article
C2 - 26122175
SN - 1521-6616
VL - 160
SP - 301
EP - 314
JO - Clinical Immunology
JF - Clinical Immunology
IS - 2
ER -