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Toward a genetic theory of childhood infectious diseases

Wednesday, January 8, 2014


Jean-Laurant Casanova, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Head of Laboratory
The Rockefeller University

Dr. Casanova is a pediatrician and immunologist by training, and has in practice become a human geneticist investigating the immunological basis of childhood infectious diseases. His group studies the human genetic determinism of pediatric infectious diseases, particularly mycobacterial diseases, invasive pneumococcal disease, herpes simplex encephalitis, chronic mucocutaneous candidiasis, severe flu, and Kaposi sarcoma. He is interested in identifying monogenic “holes” in the immune defense of otherwise healthy children who are susceptible to specific infectious diseases, work that has profound implications for and has resulted in a paradigm shift in clinical medicine and fundamental immunology.


The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably among diseases and among studies. A coherent genetic architecture of infectious diseases is lacking. We suggest that life-threatening infectious diseases in childhood, occurring in the course of primary infections, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with the high incidence of most infectious diseases in early childhood, followed by a steady decline; theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age; available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults; current knowledge of immunity to primary and secondary or latent infections; the state of the art in the clinical genetics of non-infectious pediatric and adult diseases; and evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable.

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