Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Human and Medical Genetics Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity? Alexandre Alca¨ ıs, 1,2 Lluis Quintana-Murci, 3 David S. Thaler, 4 Erwin Schurr, 5 Laurent Abel, 1,2 and Jean-Laurent Casanova 1,2 1 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Sant ´ e et de la Recherche M´ edicale, University Paris Descartes, Paris, France. 2 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York. 3 Institut Pasteur, Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Paris, France. 4 Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York. 5 McGill Centre for the Study of Host Resistance & Departments of Medicine and Human Genetics, McGill University, Montr´ eal, Qu ´ ebec, Canada Address for correspondence: Jean-Laurent Casanova, M.D., Ph.D., St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, 1230 York Avenue, New York, NY 10065. jean-laurent.casanova@rockefeller.edu 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 here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, 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 (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline; (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age; (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults; (iv) current knowledge of immunity to primary and secondary or latent infections; (v) the state of the art in the clinical genetics of noninfectious pediatric and adult diseases; and (vi) 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. Keywords: immunity; inborn errors; infectious diseases Background Clinical heterogeneity among infected patients was known to the microbiologists of the late 19th cen- tury. Nevertheless, it was not until Charles Nicolle’s discovery of asymptomatic infections between 1911 and 1917 that the question of the mechanisms un- derlying interindividual, interfamilial, and inter- population clinical variability among infected in- dividuals became a fundamental challenge in the field of infectious diseases. 1–4 If microbes are nec- essary but not sufficient for the manifestation of Re-use of this article is permitted in accordance with the Terms and Conditions set out at http:// wileyonlinelibrary.com/onlineopen#OnlineOpen Terms infectious diseases, what other factors are involved in their pathogenesis? Infectious diseases are com- monly thought to be well understood and often proposed as textbook examples of pure environ- mental diseases. However, nearly 150 years after Pas- teur’s microbial theory of disease and 100 years after Nicolle’s discovery of asymptomatic infections, it is striking that the actual pathogenesis of most infec- tious diseases remains unknown for the vast ma- jority of patients. Environmental factors, whether microbial (the pathogen) or nonmicrobial (ecolog- ical, including other microbes), and host factors, whether genetic (germline-encoded) or nongenetic (somatic and epigenetic, e.g., acquired immunity), all make potential contributions of various sizes to this complex process. 5 The respective merits of the doi: 10.1111/j.1749-6632.2010.05834.x 18 Ann. N.Y. Acad. Sci. 1214 (2010) 18–33 c  2010 New York Academy of Sciences.