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
  • # 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.