Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia
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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).
Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.
Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.
This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.
KeywordsMendelian susceptibility to mycobacterial disease Bacillus Calmette-Guérin (BCG) disseminated BCG infection, IL-12, interferon
We thank the patients and their families for participating in this study. We thank Yelena Nemirovskaya, Cécile Patissier, and Céline Desvallées for technical and secretarial assistance, and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions.
The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970-02, The Rockefeller University, and the European Research Council (ERC), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the “Investments for the future” program (grant number ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17-0005-01). F.A.S. is supported by Dallah Heathcare grant.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Research Involving Human Participants
Informed consent for participation in this study was obtained in accordance with local regulations, with approval from the IRB. The experiments described here were performed in France, in accordance with local regulations, and with the approval of the IRB of Necker Hospital for Sick Children, France.
Written informed consent was obtained from the patients.
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