ABSTRACT
Background and Aims
Inborn errors of immunity (IEI) refer to a heterogeneous group of monogenic disorders caused by germline variants that disrupt immune function. Among these conditions, immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene. c Rel is a key actor of the NF-κB pathway with major implications in the immune response. Up untill now, only two patients with confirmed pathogenic REL variants have been reported.
Methods and Results
Here, a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy. Clinical exome sequencing, confirmed by Sanger sequencing, identified a novel homozygous frameshift variant (NM_001291746.4) REL:c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon. Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact.
Conclusion
This report expands the mutational spectrum of REL and further supports the critical, non-redundant role of c-Rel in human immune homeostasis. It also highlights the central role of next generation sequencing, particularly clinical exome approaches, in the diagnosis and evolving genetic classification of IEI, enabling earlier recognition, refined subclassification, and more personalized management of affected patients.