Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds

Am J Hum Genet. 2002 Feb;70(2):336-48. doi: 10.1086/338625. Epub 2001 Dec 17.


Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Line, Transformed
  • Child
  • Child, Preschool
  • Consanguinity
  • Female
  • Founder Effect
  • Haplotypes / genetics
  • Herpesvirus 4, Human / physiology
  • Humans
  • Immune System Diseases / genetics*
  • Immune System Diseases / immunology
  • Immune System Diseases / microbiology*
  • Immune System Diseases / physiopathology
  • India
  • Infant
  • Interleukin-12 Subunit p40
  • Interleukin-12*
  • Interleukins / deficiency*
  • Interleukins / genetics*
  • Interleukins / metabolism
  • Male
  • Mutagenesis, Insertional / genetics
  • Mutation / genetics*
  • Pakistan
  • Pedigree
  • Phenotype
  • Polymorphism, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Saudi Arabia
  • Sequence Deletion / genetics


  • IL12B protein, human
  • Interleukin-12 Subunit p40
  • Interleukins
  • RNA, Messenger
  • Interleukin-12