Significance The key problem concerning pediatric infectious diseases, and more generally clinical diseases during primary infection, is their pathogenesis. A plausible and testable human genetic theory of primary infectious diseases has recently emerged, building on elegant studies in plants and animals. Three examples of monogenic resistance to common infections have been discovered. Moreover, a growing range of monogenic single-gene inborn errors of immunity, rarely Mendelian (with complete clinical penetrance) but more commonly non-Mendelian (with incomplete penetrance), have been found to underlie severe infectious diseases striking otherwise healthy children during primary infection. These findings provide a synthetic framework for inherited and infectious diseases and, more generally, for inborn and environmental conditions. This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.
【저자키워드】 immunology, Infectious diseases, Primary Immunodeficiency, Human genetics, pediatrics,