Professor Ken Smith - University of Cambridge

Professor Ken Smith - University of Cambridge

Davis Auditorium
Start Time: 
Mon, 05/08/2019 - 1:00pm
End Time: 
Mon, 05/08/2019 - 2:00pm

​Cohort-based whole genome sequencing in primary immune deficiency: a trip into genomic space

​Special seminar hosted by Professor Phil Hodgkin

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 malignancies. 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  8.2%, while a Bayesian approach (BeviMed) identified multiple potential new causal genes. Exploration of the non-coding space revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified novel PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants. 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.

Ken trained in nephrology and clinical immunology with an interest in autoimmune disease at the University of Melbourne. His PhD at the Walter and Eliza Hall Institute examined aspects of B cell immunology.   Along with his laboratory work, Professor Smith is clinically active in nephrology and transplantation at Addenbrooke’s Hospital. He established the Cambridge Immunology Strategic Research Network, directs the FoCIS Cambridge International Centre of Excellence, and led a recent successful bid for funding to establish the Cambridge Institute for Therapeutic Immunology and Infectious Disease, to open in 2018. He is a Wellcome Trust Investigator and an NIHR Senior Clinical Investigator, was elected a Fellow of the Academy of Medical Sciences in 2006, and was awarded the Lister Institute Research Prize in 2007 and the Distinguished Investigator Award of the Lupus Research Institute in 2013. Ken also helps promote the development of immunology research in Cambridge having established the Cambridge Immunology Strategic Network.