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.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

“…In recent years, it has emerged that inborn errors in genes encoding proteins of innate or cell-intrinsic immunity can underlie specific infections in otherwise healthy individuals (15,16). In this work we describe 4 patients with severe VZV infections who carried missense mutations in POLR3A and/or POLR3C, which encode subunits of the innate DNA sensor POL III.…”

“…In recent years, it has emerged that single-gene inborn errors of innate or cell-intrinsic immunity can underlie enhanced susceptibility to specific (viral) infections in otherwise healthy individuals (15,16). A striking example is that mutations in genes controlling Toll-like receptor (TLR) 3-dependent type I and III IFN-mediated immunity confer susceptibility to herpes simplex encephalitis (HSE) (17)(18)(19)(20)(21)(22).…”

Human genetic basis of interindividual variability in the course of infection

“…In this model, severe infections can gradually shape the human genome by natural selection and the spread of common variants conferring relative resistance, but only rare or private variants actually cause the genetic forms of lifethreatening disease. These ideas and data are discussed in the companion paper (161).…”

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES), caused by heterozygous dominant negative mutations of STAT3, display fewer infections, and patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) are not prone to other infections (2, 3). Finally, rare patients with inherited but idiopathic forms of CMC, referred to as CMC disease (CMCD), have been described since the late 1960s (4)(5)(6)(7)(8). These patients may display isolated CMC, but they often also display cutaneous staphylococcal disease (nonetheless referred to as CMCD) or other infectious and/or autoimmune clinical manifestations (syndromic CMCD).…”