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Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?

Authors

  • Alexandre Alcaïs,

    1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, Paris, France.
    2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
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  • Lluis Quintana-Murci,

    1. Institut Pasteur, Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Paris, France.
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  • David S. Thaler,

    1. Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
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  • Erwin Schurr,

    1. McGill Centre for the Study of Host Resistance & Departments of Medicine and Human Genetics, McGill University, Montréal, Québec, Canada
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  • Laurent Abel,

    1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, Paris, France.
    2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
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  • Jean-Laurent Casanova

    1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, Paris, France.
    2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
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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

Abstract

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.

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