Primary Immunodeficiency: mechanism and diagnosis via integrative clinical immunogenomics.

Primary Immunodeficiency (PID) has a devastating impact on the lives of patients and their families, and management is aided by genetic diagnosis. 80% of PID patients have no overt family history, and thus have been intractable to gene discovery. Our recent pilot study explored whole genome sequencing (WGS) to enhance diagnosis in PID, and found only 8% of such patients carried disease causing mutations in known PID genes. By applying new Bayesian analytical techniques, we identified multiple new PID-associated genes; causative deletions in regulatory regions; and interplay between novel high-penetrance monogenic and common variants, beginning to explain the variable penetrance of PID. We will expand this WGS PID cohort, already the world’s largest, and develop additional specialised statistical tools to incorporate deep clinical, immunophenotyping and antigen receptor repertoire data to enhance WGS analysis techniques. We will use genetic association data from immune-mediated diseases to increase power, and use genetic information to characterise the clinical features predictive of PID and enhance diagnosis. This collaborative effort will enhance understanding of PID biology, define phenotypic variability, discover new disease associated genes, increase diagnostic yield - but importantly develop mechanisms for WGS-based gene discovery in cohorts of sporadic patients, applicable beyond PID.