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Peer-reviewedCC BYJournal of human immunity

The genetic landscape of RAG deficiency: Novel and founder variants in a large Algerian cohort.

  • Brahim Belaid1,2
  • Koon-Wing Chan3
  • Jennifer Stoddard4
  • Julie Niemela4
  • Heather Kenney5
  • Adriana A De Jesus4
  • Daniel Leung3
  • Jing Yang3
  • Xing Tian Yang3
  • Abdelhak Dehimi6
  • Ouardia Drali7
  • Aida Mohand Oussaid8,9
56 more authors
  • Lydia Lamara Mahammed1,2
  • Lilya Meriem Berkani1,2
  • Hassiba Sakhri1
  • Asmaa Abed1
  • Meriem Tahir1
  • Fatma Merah1,2
  • Alaa Hamidou Benmoussa1,2
  • Ines Allam2,10
  • Lylia Djidjeli1
  • Hadia Boussaha1
  • Amina Salmi9,11
  • Sonia Yasmine Kirane9,11
  • Radia Rezzak8,9
  • Fella Lamrani8,9
  • Souhila Melzi9,12
  • Fella Dahmoune13
  • Fairouz Guerrouche9,14
  • Ahlem Mechali14
  • Amina Saad Djaballah9,15
  • Lamia Amirat9,16
  • Meriem Oussalah7
  • Yacine Inouri9,17
  • Saadeddine Dib18,19
  • Fatima Benbida18
  • Amara Zelaci20
  • Mohamed Amine Ifri21
  • Kawthar Allali22
  • Seddam Hocin Gafazi23
  • Sara Makhloufi24
  • Houda Larkat25
  • Fadela Bendaoud26,27
  • Noui Djamila27,28
  • Hamza Boucenna8,9
  • Khadidja Benallal29
  • Chahrazed El Mezouar18,19
  • Samia Bicha30
  • Rachid Bouhdjila30
  • Nadia Bensaadi31
  • Farih Mehdid9,32
  • Malek Benakli9,32
  • Rawda Aboura9,12
  • Zoulikha Zeroual9,33
  • Leila Smati9,15
  • Salih Bendeddouche19,34
  • Reda Belbouab9,35
  • Azzeddine Mekki9,14
  • Belkacem Bioud6
  • Samir Mohamed Ladj9,16

60 listed; 68 in total.

35 affiliations
  1. 1Department of Immunology, Beni Messous University Hospital Center, Algiers, Algeria.
  2. 2Faculty of Pharmacy, University of Health Sciences , Algiers, Algeria.
  3. 3Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  4. 4Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
  5. 5National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
  6. 6Department of Pediatrics, Setif University Hospital Center, Faculty of Medicine, The University of Setif 1, Setif, Algeria.
  7. 7Department of Pediatric Pulmonology and Allergology, Canastel Children's Hospital, Faculty of Medicine, The University of Oran, Oran, Algeria.
  8. 8Department of Pediatrics A, Beni Messous University Hospital Center, Algiers, Algeria.
  9. 9Faculty of Medicine, University of Health Sciences , Algiers, Algeria.
  10. 10Central Laboratory, Zeralda Burn Hospital , Algiers, Algeria.
  11. 11Department of Pediatrics B, Beni Messous University Hospital Center, Algiers, Algeria.
  12. 12Department of Pediatrics, Bab El Oued University Hospital Center, Algiers, Algeria.
  13. 13Department of Pediatrics, Bejaia University Hospital Center, Faculty of Medicine, The University of Bejaia, Bejaia, Algeria.
  14. 14Department of Pediatrics B, Hussein Dey University Hospital Center, Algiers, Algeria.
  15. 15Department of Pediatrics, Bologhine Hospital, Algiers, Algeria.
  16. 16Department of Pediatrics, Birtraria Hospital, Algiers, Algeria.
  17. 17Department of Pediatrics, Beni Messous Military Mother and Child Hospital, Algiers, Algeria.
  18. 18Department of Pediatrics, Specialized Mother and Child Hospital of Tlemcen, Tlemcen, Algeria.
  19. 19Faculty of Medicine, University of Tlemcen, Tlemcen, Algeria.
  20. 20Department of Pediatrics, El Oued Hospital, El Oued, Algeria.
  21. 21Department of Pediatrics, Thenia Hospital, Boumerdes, Algeria.
  22. 22Department of Pediatrics, Ouargla Hospital, Ouargla, Algeria.
  23. 23Department of Pediatrics, Djelfa Hospital, Djelfa, Algeria.
  24. 24Department of Pediatrics, Merouana Hospital, Batna, Algeria.
  25. 25Department of Pediatrics, Boussaada Hospital, Boussaada, Algeria.
  26. 26Department of Neonatology, Mother and Child Specialized Hospital of Batna, Algeria.
  27. 27Faculty of Medicine, The University of Batna, Algeria.
  28. 28Department of Pediatrics, Batna University Hospital Center, Batna, Algeria.
  29. 29Department of Pediatrics, Sidi Bel Abbes University Hospital Center, Faculty of Medicine, The University of Sidi Bel Abbes, Sidi Bel Abbes, Algeria.
  30. 30Department of Pediatrics B, University Hospital of Constantine, Faculty of Medicine, The University of Constantine 3, Constantine, Algeria.
  31. 31Department of Pediatrics, Tizi Ouzou University Hospital Center, Faculty of Medicine, the University of Tizi Ouzou, Tizi Ouzou, Algeria.
  32. 32Department of Hematology and Bone Morrow Transplantation, Pierre and Marie Curie Center, Algiers, Algeria.
  33. 33Department of Pediatrics A, Hussein Dey University Hospital Center, Algiers, Algeria.
  34. 34Department of Pediatrics, Tlemcen University Hospital Center, Tlemcen, Algeria.
  35. 35Department of Pediatrics, Mustapha Bacha University Hospital Center, Algiers, Algeria.
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Abstract

RAG1/RAG2 deficiency causes diverse SCID phenotypes, but large, systematically characterized cohorts from North Africa remain lacking. We retrospectively characterized 128 confirmed RAG1/RAG2-deficient patients diagnosed over 14 years in Algeria, classified per PIDTC 2022 criteria. Consanguinity was high (70.3%), with RAG2 (57.0%) outnumbering RAG1 (43.0%), a reversal of patterns reported elsewhere. Classical SCID (61.0%) and Omenn syndrome (23.4%) predominated. Two candidate founder variants (RAG1 c.519del, RAG2 c.104G>T) accounted for 76.6% of genotypes, yet identical c.519del genotypes produced three discordant phenotypes. Four novel variants and four digenic/oligogenic cases broadened the molecular spectrum. Despite a short diagnostic delay, mortality was 89.1%, driven primarily by near-absent HSCT access (2.3%). This study expands the molecular and clinical spectrum of RAG deficiency in an underrepresented population, revealing a reversed RAG1/RAG2 ratio and phenotypic heterogeneity despite shared founder genotypes. These findings prioritize functional validation of uncertain-significance variants and underscore the need for NBS and expanded transplant access to translate diagnosis into survival.

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Cite

BibTeXRIS
BibTeX
@article{belaid2026genetic,
  title = {{The genetic landscape of RAG deficiency: Novel and founder variants in a large Algerian cohort.}},
  author = {Brahim Belaid and Koon-Wing Chan and Jennifer Stoddard and Julie Niemela and Heather Kenney and Adriana A De Jesus and Daniel Leung and Jing Yang and Xing Tian Yang and Abdelhak Dehimi and Ouardia Drali and Aida Mohand Oussaid and Lydia Lamara Mahammed and Lilya Meriem Berkani and Hassiba Sakhri and Asmaa Abed and Meriem Tahir and Fatma Merah and Alaa Hamidou Benmoussa and Ines Allam and Lylia Djidjeli and Hadia Boussaha and Amina Salmi and Sonia Yasmine Kirane and Radia Rezzak and Fella Lamrani and Souhila Melzi and Fella Dahmoune and Fairouz Guerrouche and Ahlem Mechali and Amina Saad Djaballah and Lamia Amirat and Meriem Oussalah and Yacine Inouri and Saadeddine Dib and Fatima Benbida and Amara Zelaci and Mohamed Amine Ifri and Kawthar Allali and Seddam Hocin Gafazi and Sara Makhloufi and Houda Larkat and Fadela Bendaoud and Noui Djamila and Hamza Boucenna and Khadidja Benallal and Chahrazed El Mezouar and Samia Bicha and Rachid Bouhdjila and Nadia Bensaadi and Farih Mehdid and Malek Benakli and Rawda Aboura and Zoulikha Zeroual and Leila Smati and Salih Bendeddouche and Reda Belbouab and Azzeddine Mekki and Belkacem Bioud and Samir Mohamed Ladj},
  journal = {Journal of human immunity},
  year = {2026},
  month = oct,
  doi = {10.70962/jhi.20260168},
  url = {https://europepmc.org/article/MED/42929759},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The genetic landscape of RAG deficiency: Novel and founder variants in a large Algerian cohort.
AU  - Brahim Belaid
AU  - Koon-Wing Chan
AU  - Jennifer Stoddard
AU  - Julie Niemela
AU  - Heather Kenney
AU  - Adriana A De Jesus
AU  - Daniel Leung
AU  - Jing Yang
AU  - Xing Tian Yang
AU  - Abdelhak Dehimi
AU  - Ouardia Drali
AU  - Aida Mohand Oussaid
AU  - Lydia Lamara Mahammed
AU  - Lilya Meriem Berkani
AU  - Hassiba Sakhri
AU  - Asmaa Abed
AU  - Meriem Tahir
AU  - Fatma Merah
AU  - Alaa Hamidou Benmoussa
AU  - Ines Allam
AU  - Lylia Djidjeli
AU  - Hadia Boussaha
AU  - Amina Salmi
AU  - Sonia Yasmine Kirane
AU  - Radia Rezzak
AU  - Fella Lamrani
AU  - Souhila Melzi
AU  - Fella Dahmoune
AU  - Fairouz Guerrouche
AU  - Ahlem Mechali
AU  - Amina Saad Djaballah
AU  - Lamia Amirat
AU  - Meriem Oussalah
AU  - Yacine Inouri
AU  - Saadeddine Dib
AU  - Fatima Benbida
AU  - Amara Zelaci
AU  - Mohamed Amine Ifri
AU  - Kawthar Allali
AU  - Seddam Hocin Gafazi
AU  - Sara Makhloufi
AU  - Houda Larkat
AU  - Fadela Bendaoud
AU  - Noui Djamila
AU  - Hamza Boucenna
AU  - Khadidja Benallal
AU  - Chahrazed El Mezouar
AU  - Samia Bicha
AU  - Rachid Bouhdjila
AU  - Nadia Bensaadi
AU  - Farih Mehdid
AU  - Malek Benakli
AU  - Rawda Aboura
AU  - Zoulikha Zeroual
AU  - Leila Smati
AU  - Salih Bendeddouche
AU  - Reda Belbouab
AU  - Azzeddine Mekki
AU  - Belkacem Bioud
AU  - Samir Mohamed Ladj
PY  - 2026
DA  - 2026/10/26
JO  - Journal of human immunity
DO  - 10.70962/jhi.20260168
UR  - https://europepmc.org/article/MED/42929759
AB  - RAG1/RAG2 deficiency causes diverse SCID phenotypes, but large, systematically characterized cohorts from North Africa remain lacking. We retrospectively characterized 128 confirmed RAG1/RAG2-deficient patients diagnosed over 14 years in Algeria, classified per PIDTC 2022 criteria. Consanguinity was high (70.3%), with RAG2 (57.0%) outnumbering RAG1 (43.0%), a reversal of patterns reported elsewhere. Classical SCID (61.0%) and Omenn syndrome (23.4%) predominated. Two candidate founder variants (RAG1 c.519del, RAG2 c.104G>T) accounted for 76.6% of genotypes, yet identical c.519del genotypes produced three discordant phenotypes. Four novel variants and four digenic/oligogenic cases broadened the molecular spectrum. Despite a short diagnostic delay, mortality was 89.1%, driven primarily by near-absent HSCT access (2.3%). This study expands the molecular and clinical spectrum of RAG deficiency in an underrepresented population, revealing a reversed RAG1/RAG2 ratio and phenotypic heterogeneity despite shared founder genotypes. These findings prioritize functional validation of uncertain-significance variants and underscore the need for NBS and expanded transplant access to translate diagnosis into survival.
SN  - 3065-8993
ER  -