Variation in susceptibility to infection and autoimmunity across the human population remains incompletely understood. While genetics has revealed important pathways involved in this, our knowledge of the impact of genetic variation immune susceptibility and tolerance remains hampered by knowledge and data gaps. These are related to the nature of the clinical syndromes (variable clinical phenotypes with incomplete clinical penetrance and varying age of onset etc.), to methodological variation (e.g. a focus on familial co-segregation of rare germline variants in the coding space (<1/104) or on common variants in GWAS (>1/20-100) when much lies between) and to lack of standardised “functional” immune phenotyping.

We have tried to fill some of these gaps by studying Inborn Errors of Immunity (IEI, aka Primary Immune Deficiency), a group of disorders characterised by recurrent infection, autoimmunity and malignancy. While over 600 genetic causes of IEIs have been described >70% of patients do not receive a genetic diagnosis. We explored whole genome sequencing in a UK-wide study in adult IEI, using Bayesian analytical techniques (without familial co-segregation) to identify new IEI-associated genes, exploring the non-coding space and defining the impact of common and intermediate frequency variants on IEI and on immune variation in the normal population. This defined a number of genes causing new monogenic diseases but also impacting infection risk in the broader population. Expanding these approaches and integrating new functional immunophenotyping, together with exploring non-genetic impacts, is set to revolutionise our understanding of human immune variation and disease susceptibility.