Whole-genome sequencing of a sporadic primary immunodeficiency cohort

, James E. D. Thaventhiran (Lead / Corresponding author), 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 GordinsHelen 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, Julie Anderson, Paul Brennan, Richard Brown, Nicola S. Curry, E. G. Davies, Dafydd Gareth Evans, Claire Harris, Stephen Hughes, Julie Jones, Wei Li, Mark I. McCarthy, Andrew S. C. Rice, Cathal L. Steele, David C. Thomas, John A. Todd, Natalie van Zuydam, David J. Williams, Kenneth G.C. Smith (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    133 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)90-95
    Number of pages6
    Issue number7814
    Early online date6 May 2020
    Publication statusPublished - 2 Jul 2020

    ASJC Scopus subject areas

    • General


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