Inherited interleukin-12 deficiency

IL12B genotype and clinical phenotype of 13 patients from six kindreds

Capucine Picard, Claire Fieschi, Frédéric Altare, Suliman Al-Jumaah, Sami Al-Hajjar, Jacqueline Feinberg, Stéphanie Dupuis, Claire Soudais, Ibrahim Zaid Al-Mohsen, Emmanuelle Génin, David Lammas, Dinakantha S. Kumararatne, Tony Leclerc, Arash Rafii Tabrizi, Husn Frayha, Belinda Murugasu, Lee Bee Wah, Raja Sinniah, Michael Loubser, Emi Okamoto & 4 others Abdulaziz Al-Ghonaium, Haysam Tufenkeji, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-γ 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 ∼700 and ∼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.

Original languageEnglish
Pages (from-to)336-348
Number of pages13
JournalAmerican Journal of Human Genetics
Volume70
Issue number2
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Interleukin-12
Genotype
Phenotype
Salmonella Infections
Nocardia asteroides
Cytokines
Founder Effect
Recurrence
Nontuberculous Mycobacteria
Salmonella enteritidis
Mutation
Inborn Genetic Diseases
Saudi Arabia
Phagocytes
Infection
Mycobacterium tuberculosis
Salmonella
Dendritic Cells
Haplotypes
Interferons

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Picard, C., Fieschi, C., Altare, F., Al-Jumaah, S., Al-Hajjar, S., Feinberg, J., ... Casanova, J. L. (2002). Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. American Journal of Human Genetics, 70(2), 336-348. https://doi.org/10.1086/338625

Inherited interleukin-12 deficiency : IL12B genotype and clinical phenotype of 13 patients from six kindreds. / Picard, Capucine; Fieschi, Claire; Altare, Frédéric; Al-Jumaah, Suliman; Al-Hajjar, Sami; Feinberg, Jacqueline; Dupuis, Stéphanie; Soudais, Claire; Al-Mohsen, Ibrahim Zaid; Génin, Emmanuelle; Lammas, David; Kumararatne, Dinakantha S.; Leclerc, Tony; Tabrizi, Arash Rafii; Frayha, Husn; Murugasu, Belinda; Wah, Lee Bee; Sinniah, Raja; Loubser, Michael; Okamoto, Emi; Al-Ghonaium, Abdulaziz; Tufenkeji, Haysam; Abel, Laurent; Casanova, Jean Laurent.

In: American Journal of Human Genetics, Vol. 70, No. 2, 2002, p. 336-348.

Research output: Contribution to journalArticle

Picard, C, Fieschi, C, Altare, F, Al-Jumaah, S, Al-Hajjar, S, Feinberg, J, Dupuis, S, Soudais, C, Al-Mohsen, IZ, Génin, E, Lammas, D, Kumararatne, DS, Leclerc, T, Tabrizi, AR, Frayha, H, Murugasu, B, Wah, LB, Sinniah, R, Loubser, M, Okamoto, E, Al-Ghonaium, A, Tufenkeji, H, Abel, L & Casanova, JL 2002, 'Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds', American Journal of Human Genetics, vol. 70, no. 2, pp. 336-348. https://doi.org/10.1086/338625
Picard, Capucine ; Fieschi, Claire ; Altare, Frédéric ; Al-Jumaah, Suliman ; Al-Hajjar, Sami ; Feinberg, Jacqueline ; Dupuis, Stéphanie ; Soudais, Claire ; Al-Mohsen, Ibrahim Zaid ; Génin, Emmanuelle ; Lammas, David ; Kumararatne, Dinakantha S. ; Leclerc, Tony ; Tabrizi, Arash Rafii ; Frayha, Husn ; Murugasu, Belinda ; Wah, Lee Bee ; Sinniah, Raja ; Loubser, Michael ; Okamoto, Emi ; Al-Ghonaium, Abdulaziz ; Tufenkeji, Haysam ; Abel, Laurent ; Casanova, Jean Laurent. / Inherited interleukin-12 deficiency : IL12B genotype and clinical phenotype of 13 patients from six kindreds. In: American Journal of Human Genetics. 2002 ; Vol. 70, No. 2. pp. 336-348.
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abstract = "Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-γ 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-Gu{\'e}rin (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 ∼700 and ∼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.",
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T1 - Inherited interleukin-12 deficiency

T2 - IL12B genotype and clinical phenotype of 13 patients from six kindreds

AU - Picard, Capucine

AU - Fieschi, Claire

AU - Altare, Frédéric

AU - Al-Jumaah, Suliman

AU - Al-Hajjar, Sami

AU - Feinberg, Jacqueline

AU - Dupuis, Stéphanie

AU - Soudais, Claire

AU - Al-Mohsen, Ibrahim Zaid

AU - Génin, Emmanuelle

AU - Lammas, David

AU - Kumararatne, Dinakantha S.

AU - Leclerc, Tony

AU - Tabrizi, Arash Rafii

AU - Frayha, Husn

AU - Murugasu, Belinda

AU - Wah, Lee Bee

AU - Sinniah, Raja

AU - Loubser, Michael

AU - Okamoto, Emi

AU - Al-Ghonaium, Abdulaziz

AU - Tufenkeji, Haysam

AU - Abel, Laurent

AU - Casanova, Jean Laurent

PY - 2002

Y1 - 2002

N2 - Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-γ 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 ∼700 and ∼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.

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