The IL2RB gene encodes the beta subunit of the interleukin-2 (IL2) receptor, which transmits signals from the cytokines IL-2 and IL-15. IL2RB shows constitutive or induced expression on various types of immune cells, including CD4+ T regulatory cells, CD4+ and CD8+ T cells, B cells, and natural killer cells. IL2RB cytoplasmic domain is essential for JAK1/3 signaling. Biallelic loss-of-function variants typically cause autosomal recessive immunodeficiency. Here, we describe a patient with a novel heterozygous splice site variant and severe immune dysregulation.
Clinical evaluation and whole exome sequencing were performed. Variant classification followed the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In silico predictions were used to assess the molecular consequences.
A 4-year-old girl born to non-consanguineous parents presented with neonatal diabetes requiring insulin-pump therapy (anti-glutamic acid decarboxylase antibodies positive), autoimmune hypothyroidism (anti-thyroglobulin and anti-thyroperoxidase antibodies positive), autoimmune hemolytic anemia (direct Coombs positive), chronic diarrhea consistent with inflammatory bowel disease, and bullous pemphigoid (anti-bullous pemphigoid antibodies positive). This last manifestation was refractory to high-dose intravenous immunoglobulin, corticosteroids, dapsone, and rituximab, with only partial improvement; clinical stabilization was achieved after dupilumab plus palliative care. Whole exome sequencing identified a heterozygous IL2RB splice site variant (c.903+1G>T), absent from gnomAD and classified as likely pathogenic (PVS1, PM2). The variant disrupts the canonical donor site of intron 9, and in silico splicing predictors indicate activation of a cryptic donor site 26 nt upstream in exon 9, generating a frameshift and premature stop codon located within the last exon, thereby predicted to escape nonsense-mediated decay. The predicted truncated protein lacks most of the intracellular domain, likely compromising JAK1/3-mediated signaling.
This case raises the possibility of a dominant-negative or haploinsufficient mechanism of IL2RB-related disease. Functional studies are needed to confirm the impact on receptor signaling and clarify the inheritance pattern.
