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.