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Lookup NU author(s): Professor Kevin MarchbankORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2020.
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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 malignancies1,2,3. 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.
Author(s): Thaventhiran JED, Allen HL, Marchbank KJ, Smith KGC
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2020
Volume: 583
Pages: 90-95
Print publication date: 02/07/2020
Online publication date: 06/05/2020
Acceptance date: 26/02/2020
Date deposited: 14/05/2020
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41586-020-2265-1
DOI: 10.1038/s41586-020-2265-1
Notes: included as part PMG consortium
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