RT Journal Article
SR Electronic
T1 Whole Genome Sequencing of Primary Immunodeficiency reveals a role for common and rare variants in coding and non-coding sequences
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 499988
DO 10.1101/499988
A1 James E. D. Thaventhiran
A1 Hana Lango Allen
A1 Oliver S. Burren
A1 James H. R. Farmery
A1 Emily Staples
A1 Zinan Zhang
A1 William Rae
A1 Daniel Greene
A1 Ilenia Simeoni
A1 Jesmeen Maimaris
A1 Chris Penkett
A1 Jonathan Stephens
A1 Sri V.V. Deevi
A1 Alba Sanchis-Juan
A1 Nicholas S Gleadall
A1 Moira J. Thomas
A1 Ravishankar B. Sargur
A1 Pavels Gordins
A1 Helen E. Baxendale
A1 Matthew Brown
A1 Paul Tuijnenburg
A1 Austen Worth
A1 Steven Hanson
A1 Rachel Linger
A1 Matthew S. Buckland
A1 Paula J. Rayner-Matthews
A1 Kimberly C. Gilmour
A1 Crina Samarghitean
A1 Suranjith L. Seneviratne
A1 Paul A. Lyons
A1 David M. Sansom
A1 Andy G. Lynch
A1 Karyn Megy
A1 Eva Ellinghaus
A1 David Ellinghaus
A1 Silje F. Jorgensen
A1 Tom H Karlsen
A1 Kathleen E. Stirrups
A1 Antony J. Cutler
A1 Dinakantha S. Kumararatne
A1 NBR-RD PID Consortium, NIHR BioResource
A1 Sinisa Savic
A1 Siobhan O. Burns
A1 Taco W. Kuijpers
A1 Ernest Turro
A1 Willem H. Ouwehand
A1 Adrian J. Thrasher
A1 Kenneth G. C. Smith
YR 2018
UL http://biorxiv.org/content/early/2018/12/21/499988.abstract
AB Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 subjects. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 8.2%, while a Bayesian approach (BeviMed1) identified multiple potential new disease-associated genes. Exploration of the non-coding space revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified novel PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways determining variation in human immune responsiveness.