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

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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Publication Details

Journal
Journal of Human Immunity
Published
2026-10-26
DOI
https://doi.org/10.70962/jhi.20260168
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Fatma Merah, Nadia Bensaadi, Salih Bendeddouche, Aida Mohand Oussaid et al.
Journal of Human Immunity
Immunodeficiency and Autoimmune Disorders
article

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

Fatma Merah, Nadia Bensaadi, Salih Bendeddouche, Aida Mohand Oussaid, Lamia Amirat, Asmahane Ladjouze, Ourida Gacem, Nafissa Keltoum Benhalla, Zoulikha Zeroual, Heather Kenney, Yacine Inouri, Luigi Daniele Notarangelo, Brahim Belaid, Mohamed Amine Ifri, Reda Belbouab, Amina Saad-Djaballah, Jaime S. Rosa Duque, Samia Bicha, Farih Mehdid, Meriem Oussalah, Lilya Meriem Berkani, Asmaa Abed, Sergio D. Rosenzweig, YL Lau, Azzeddine Mekki, Adriana A. de Jesus, Amara Zelaci, Réda Djidjik, Ouardia Ibsaine, Julie E. Niemela, Djamila Noui, Lydia Lamara Mahammed, Koon Wing Chan, Malek Benakli, Rawda Aboura, Jing Yang, Souhila Melzi, Belkacem Bioud, Jennifer L. Stoddard, Amina Salmi, Rachid Bouhdjila, Daniel Leung, Ines Allam, Xingtian Yang, Khadidja BENALLAL, Sara Makhloufi, Hassiba Sakhri, Lylia Djidjeli, Hadia Boussaha, Sonia Yasmine KIRANE, Hamza Boucenna, Houda Larkat, Abdelhak Dehimi, Fella Dahmoune, Saadeddine Dib, Samir Mohamed Ladj, Chahrazed El Mezouar, Kawthar Allali, Fairouz Guerrouche, Meriem Tahir, Fella Lamrani, Fadela Bendaoud, Leila Smati, Ahlem Mechali, Seddam Hocin Gafazi, Radia Rezzak, Alaa Hamidou Benmoussa, Fatima Benbida
article en

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.

Journal of Human ImmunityVol. 3(1)
National Institutes of Health (US), Université Oran 1 Ahmed Ben Bella (DZ), University of Batna 1 (DZ), University of Béjaïa (DZ), University of Algiers Benyoucef Benkhedda (DZ), University of Abou Bekr Belkaïd (DZ), University of Boumerdes (DZ), Sorbonne Université (FR), University Ferhat Abbas of Setif (DZ), Ziane Achour University of Djelfa (DZ), Centre Hospito Universitaire de Sétif (DZ), University of Algiers 3 (DZ), Université Djilali de Sidi Bel Abbès (DZ), Mother Hospital (IN), National Institute of Allergy and Infectious Diseases (US), Dynamic Systems (United States) (US), Centre Hospitalo-Universitaire Bab El Oued (DZ), Hôpital Mustapha Pacha (DZ), National Institutes of Health Clinical Center (US), Mouloud Mammeri University of Tizi-Ouzou (DZ), University of Batna 2 (DZ), University of Constantine 3 (DZ), University of Hong Kong (HK)
National Institutes of Health
Openalex Percentile: Top 18%
Immunodeficiency and Autoimmune Disorders
DOIOpen Access PDFOpenAlex
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