Understanding the pathophysiology of monogenic primary immunodeficiency (PID) with atopic presentation has pivotal implications for intervention strategies and potentially wider polygenic atopic-related traits. This review will discuss advances in gene discovery arising from monogenic defects at the interface between PID and atopy, notably the hyper-IgE syndromes.
Key molecular pathways underlying development of primary atopic diseases have recently been proposed. We test this classification through reviewing novel genes reported in the last 2 years and compare insights from pathway-analysis of genome-wide association studies (GWAS) of atopic-related traits.
Growing access to next-generation sequencing (NGS) has resulted in a surge in gene discovery, highlighting the utility and some pitfalls of this approach in clinical practice. The variability of presenting phenotypes reveals important gene-dosage effects. This has important implications for therapeutic strategies such as protein stabilization and modulators of JAK-STAT or TH2-cytokine signalling. We also consider the therapeutic implications raised by CARD11 deficiency, and wider applications of NGS including polygenic risk score in atopy.
Disorders presenting at the interface between PID and allergy are often difficult to diagnose, with serious consequences if missed. Application of NGS has already provided critical insights to pathways enabling targeted therapeutic interventions, and potential wider translation to polygenic disorders.
aImmunodeficiency Centre for Wales, University Hospital of Wales, Cardiff University, Cardiff
bDepartment of Medicine, University of Cambridge, Cambridge, UK
cDepartment of Immunology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
dCenter for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, Freiburg im Breisgau, Germany
Correspondence to Mark J. Ponsford, Immunodeficiency Centre for Wales, University Hospital of Wales; Cardiff University, Cardiff, UK. E-mail: firstname.lastname@example.org
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