Whole genome sequencing of a sporadic primary immunodeficiency cohort

Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of 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 PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation 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 variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.Funding for the NIHR-BioResource was provided by the National Institute for Health Research (NIHR, grant number RG65966). We gratefully acknowledge the participation of all NIHR BioResource volunteers, and thank the NIHR BioResource centre and staff for their contribution. JEDT is supported by the MRC (RG95376 and MR/L006197/1). AJT is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. KGCS is supported by the Medical Research Council (program grant MR/L019027) and is a Wellcome Investigator. AJC was supported by the Wellcome [091157/Z/10/Z], [107212/Z/15/Z], [100140/Z/12/Z], [203141/Z/16/Z]; JDRF [9-2011-253], [5-SRA-2015-130-A-N]; NIHR Oxford Biomedical Research Centre and the NIHR Cambridge Biomedical Research Centre. EE has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement no 609020- Scientia Fellows. ER is supported supported by the Wellcome Trust [201250/Z/16/Z]. DE is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A; GB-XMAP grant 01ZX1709) and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany`s Excellence EXC 2167-390884018. The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the National Institute for Health Research (NIHR). This research was co-funded by the support listed above and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC)