2. Academic Validation
  3. Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Whole-genome sequencing of a sporadic primary immunodeficiency cohort

  • Nature. 2020 Jul;583(7814):90-95. doi: 10.1038/s41586-020-2265-1.
James E D Thaventhiran # 1 2 3,  Hana Lango Allen # 4 5 6 7,  Oliver S Burren # 8 9,  William Rae # 8 9,  Daniel Greene 4 6 10,  Emily Staples 9,  Zinan Zhang 8 9 11,  James H R Farmery 10 12,  Ilenia Simeoni 4 6,  Elizabeth Rivers 13 14,  Jesmeen Maimaris 13 14,  Christopher J Penkett 4 6,  Jonathan Stephens 4 5 6,  Sri V V Deevi 4 6,  Alba Sanchis-Juan 4 5 6,  Nicholas S Gleadall 4 5,  Moira J Thomas 15 16,  Ravishankar B Sargur 17 18,  Pavels Gordins 19,  Helen E Baxendale 8 9 20,  Matthew Brown 4 6,  Paul Tuijnenburg 21 22,  Austen Worth 13 14,  Steven Hanson 23 24,  Rachel J Linger 6 25,  Matthew S Buckland 23 24,  Paula J Rayner-Matthews 4 6,  Kimberly C Gilmour 13 14,  Crina Samarghitean 4 6,  Suranjith L Seneviratne 23 24,  David M Sansom 23 24,  Andy G Lynch 12 26 27,  Karyn Megy 4 6,  Eva Ellinghaus 28,  David Ellinghaus 29 30,  Silje F Jorgensen 31 32,  Tom H Karlsen 28,  Kathleen E Stirrups 4 6,  Antony J Cutler 33,  Dinakantha S Kumararatne 9 34,  Anita Chandra 8 9 34,  J David M Edgar 35 36,  Archana Herwadkar 37,  Nichola Cooper 38,  Sofia Grigoriadou 39,  Aarnoud P Huissoon 40 41,  Sarah Goddard 42,  Stephen Jolles 43,  Catharina Schuetz 44,  Felix Boschann 45,  Primary Immunodeficiency Consortium for the NIHR Bioresource,  Paul A Lyons 8 9,  Matthew E Hurles 46,  Sinisa Savic 47 48 49,  Siobhan O Burns 23 24,  Taco W Kuijpers 21 22 50,  Ernest Turro 4 5 6 10,  Willem H Ouwehand 4 5 6 51,  Adrian J Thrasher 13 14,  Kenneth G C Smith 52 53
Affiliations

Affiliation

  • # Contributed equally.
PMID: 32499645 DOI: 10.1038/s41586-020-2265-1
Abstract

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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