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Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?
Article first published online: 22 NOV 2010
© 2010 New York Academy of Sciences
Annals of the New York Academy of Sciences
Volume 1214, The Year in Human and Medical Genetics pages 18–33, December 2010
How to Cite
Alcaïs, A., Quintana-Murci, L., Thaler, D. S., Schurr, E., Abel, L. and Casanova, J.-L. (2010), Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?. Annals of the New York Academy of Sciences, 1214: 18–33. doi: 10.1111/j.1749-6632.2010.05834.x
- Issue published online: 22 DEC 2010
- Article first published online: 22 NOV 2010
- inborn errors;
- infectious diseases
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.