Abdulrahman N Alodayani1, Abdulnasir M Al-Otaibi1, Caroline Deswarte2,3, Husn Habib Frayha4, Matthieu Bouaziz2,3, Maryam AlHelale1, Tom Le Voyer2,3, Alejandro Nieto-Patlan2,3, Vimel Rattina2,3, Mofareh AlZahrani5, Rabih Halwani4,6, Fahad Al Sohime6, Hamoud Al-Mousa4, Saleh Al-Muhsen4,6, Sami H Alhajjar4, Nabil S Dhayhi7, Laurent Abel2,3,8, Jean-Laurent Casanova2,3,8,9,10, Ibrahim Bin-Hussain4, May S AlBarrak1, Suliman A Al-Jumaah4, Jacinta Bustamante11,12,13,14. 1. Division of Infectious Diseases, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France. 3. Paris Descartes University, Paris, France. 4. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 5. Section of Pediatric, Allergy and Immunology, Children Specialized Hospital, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 6. Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 7. Department of Pediatrics, King Fahad Specialist Hospital, Gizan, Saudi Arabia. 8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York City, NY, USA. 9. Howard Hughes Medical Institute, New York City, NY, USA. 10. Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, France. 11. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr. 12. Paris Descartes University, Paris, France. jacinta.bustamante@inserm.fr. 13. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York City, NY, USA. jacinta.bustamante@inserm.fr. 14. Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris AP-HP, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr.
Abstract
PURPOSE: 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). METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. RESULTS: 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. CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.
PURPOSE: 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). METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. RESULTS: 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. CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.
Authors: F Altare; D Lammas; P Revy; E Jouanguy; R Döffinger; S Lamhamedi; P Drysdale; D Scheel-Toellner; J Girdlestone; P Darbyshire; M Wadhwa; H Dockrell; M Salmon; A Fischer; A Durandy; J L Casanova; D S Kumararatne Journal: J Clin Invest Date: 1998-12-15 Impact factor: 14.808
Authors: Alexandra Y Kreins; Michael J Ciancanelli; Satoshi Okada; Xiao-Fei Kong; Noé Ramírez-Alejo; Sara Sebnem Kilic; Jamila El Baghdadi; Shigeaki Nonoyama; Seyed Alireza Mahdaviani; Fatima Ailal; Aziz Bousfiha; Davood Mansouri; Elma Nievas; Cindy S Ma; Geetha Rao; Andrea Bernasconi; Hye Sun Kuehn; Julie Niemela; Jennifer Stoddard; Paul Deveau; Aurelie Cobat; Safa El Azbaoui; Ayoub Sabri; Che Kang Lim; Mikael Sundin; Danielle T Avery; Rabih Halwani; Audrey V Grant; Bertrand Boisson; Dusan Bogunovic; Yuval Itan; Marcela Moncada-Velez; Ruben Martinez-Barricarte; Melanie Migaud; Caroline Deswarte; Laia Alsina; Daniel Kotlarz; Christoph Klein; Ingrid Muller-Fleckenstein; Bernhard Fleckenstein; Valerie Cormier-Daire; Stefan Rose-John; Capucine Picard; Lennart Hammarstrom; Anne Puel; Saleh Al-Muhsen; Laurent Abel; Damien Chaussabel; Sergio D Rosenzweig; Yoshiyuki Minegishi; Stuart G Tangye; Jacinta Bustamante; Jean-Laurent Casanova; Stéphanie Boisson-Dupuis Journal: J Exp Med Date: 2015-08-24 Impact factor: 14.307