The genetic landscape of RAG deficiency: Novel and founder variants in a large Algerian cohort
Brahim Belaid, Koon-Wing Chan, Jennifer Stoddard, Julie Niemela, Heather Kenney, Adriana A. De Jesus, Daniel Leung, Jing Yang, Xing Tian Yang, Abdelhak Dehimi, Ouardia Drali, Aida Mohand Oussaid, Lydia Lamara Mahammed, Lilya Meriem Berkani, Hassiba Sakhri, Asmaa Abed, Meriem Tahir, Fatma Merah, Alaa Hamidou Benmoussa, Ines Allam, Lylia Djidjeli, Hadia Boussaha, Amina Salmi, Sonia Yasmine Kirane, Radia Rezzak, Fella Lamrani, Souhila Melzi, Fella Dahmoune, Fairouz Guerrouche, Ahlem Mechali, Amina Saad Djaballah, Lamia Amirat, Meriem Oussalah, Yacine Inouri, Saadeddine Dib, Fatima Benbida, Amara Zelaci, Mohamed Amine Ifri, Kawthar Allali, Seddam Hocin Gafazi, Sara Makhloufi, Houda Larkat, Fadela Bendaoud, Noui Djamila, Hamza Boucenna, Khadidja Benallal, Chahrazed El Mezouar, Samia Bicha, Rachid Bouhdjila, Nadia Bensaadi, Farih Mehdid, Malek Benakli, Rawda Aboura, Zoulikha Zeroual, Leila Smati, Salih Bendeddouche, Reda Belbouab, Azzeddine Mekki, Belkacem Bioud, Samir Mohamed Ladj, Asmahane Ladjouze, Ourida Gacem, Nafissa Benhalla, Jaime Sou Rosa Duque, Sergio Rosenzweig, Yu Lung Lau, Luigi Daniele Notarangelo, Reda DjidjikRAG1/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.