A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.

Area of Science:

• Immunology
• Genetics
• Rare Diseases

Background:

• Inborn errors of immunity (IEI) are monogenic disorders affecting immune function.
• Immunodeficiency 92 (IMD92) is an extremely rare autosomal recessive disorder caused by pathogenic variants in the REL gene, affecting the NF-κB pathway.
• Only two patients with confirmed pathogenic REL variants have been previously reported.

Purpose of the Study:

• To describe a third case of IMD92.
• To expand the mutational spectrum of the REL gene.
• To emphasize the role of genetic sequencing in diagnosing IEI.

Main Methods:

• Clinical exome sequencing followed by Sanger sequencing.
• Western blot analysis of peripheral blood mononuclear cells.

Main Results:

• A novel homozygous frameshift variant (REL:c.24del p.(Tyr9Ilefs*2)) was identified in a 5-year-old child with combined immunodeficiency.
• The patient presented with chronic diarrhea, recurrent opportunistic infections, craniosynostosis, language delay, and epilepsy.
• The identified variant led to a severe reduction in c-Rel protein expression, confirming its functional impact.

Conclusions:

• This case expands the known REL mutational spectrum for IMD92.
• The findings underscore the critical role of c-Rel in human immune homeostasis.
• Next-generation sequencing, particularly clinical exome sequencing, is crucial for diagnosing and classifying IEI, enabling personalized patient management.