Severe infectious diseases of childhood as monogenic inborn errors of immunity

Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):E7128-37. doi: 10.1073/pnas.1521651112. Epub 2015 Nov 30.


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.

Publication types

  • Review

MeSH terms

  • Adolescent
  • Candidiasis, Chronic Mucocutaneous / genetics
  • Candidiasis, Chronic Mucocutaneous / immunology
  • Child
  • Complement System Proteins / genetics
  • Encephalitis, Herpes Simplex / genetics
  • Encephalitis, Herpes Simplex / immunology
  • Epidermodysplasia Verruciformis / genetics
  • Epidermodysplasia Verruciformis / immunology
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / immunology*
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology*
  • Infections / genetics*
  • Infections / immunology*
  • Influenza, Human / genetics
  • Influenza, Human / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology
  • Malaria / genetics
  • Malaria / immunology
  • Models, Genetic
  • Models, Immunological
  • Mycobacterium Infections / genetics
  • Mycobacterium Infections / immunology
  • Neisseria / immunology
  • Neisseria / pathogenicity
  • Pneumococcal Infections / genetics
  • Pneumococcal Infections / immunology
  • Tinea / genetics
  • Tinea / immunology
  • Young Adult


  • Interferon-gamma
  • Complement System Proteins