Severe infectious diseases of childhood as monogenic inborn errors of immunity

Abstract

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.

Keywords: human genetics; immunology; infectious diseases; pediatrics; primary immunodeficiency.

Fig. 1.

The genetic component of human infectious diseases, according to age. Schematic representation of a hypothetical, age-dependent, human genetic architecture of infectious diseases. We suggest that single-gene human variants make an important contribution to the determinism of life-threatening infectious diseases in the course of primary infection, which occurs most often in childhood. In this model, single-gene inborn errors of immunity are more often monogenic than Mendelian, with incomplete penetrance and variable expressivity accounting for infectious diseases being more often sporadic than familial. By contrast, predisposition to severe infectious diseases in the course of microbial reactivation from latency or secondary infection, typically in adults, is less influenced by germline human genetic variations, resulting in a more complex and less monogenic component. Somatic and epigenetic processes are likely to play a greater role in older individuals. Reproduced from ref. .