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Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Artikel i vetenskaplig tidskrift
Författare James E D Thaventhiran
Hana Lango Allen
Oliver S Burren
William Rae
Daniel Greene
Emily Staples
Zinan Zhang
James H R Farmery
Ilenia Simeoni
Elizabeth Rivers
Jesmeen Maimaris
Christopher J Penkett
Jonathan Stephens
Sri V V Deevi
Alba Sanchis-Juan
Nicholas S Gleadall
Moira J Thomas
Ravishankar B Sargur
Pavels Gordins
Helen E Baxendale
Matthew Brown
Paul Tuijnenburg
Austen Worth
Steven Hanson
Rachel J Linger
Matthew S Buckland
Paula J Rayner-Matthews
Kimberly C Gilmour
Crina Samarghitean
Suranjith L Seneviratne
David M Sansom
Andy G Lynch
Karyn Megy
Eva Ellinghaus
David Ellinghaus
Silje F Jorgensen
Tom H Karlsen
Kathleen E Stirrups
Antony J Cutler
Dinakantha S Kumararatne
Anita Chandra
J David M Edgar
Archana Herwadkar
Nichola Cooper
Sofia Grigoriadou
Aarnoud P Huissoon
Sarah Goddard
Stephen Jolles
Catharina Schuetz
Felix Boschann
Paul A Lyons
Matthew E Hurles
Sinisa Savic
Siobhan O Burns
Taco W Kuijpers
Ernest Turro
Willem H Ouwehand
Adrian J Thrasher
Kenneth G C Smith
Hanns-Ulrich Marschall
Publicerad i Nature
Volym 583
Nummer/häfte 7814
Sidor 90-95
ISSN 1476-4687
Publiceringsår 2020
Publicerad vid
Sidor 90-95
Språk en
Länkar dx.doi.org/10.1038/s41586-020-2265-...
Ämneskategorier Klinisk medicin


Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most 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 malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization 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 the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

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