HELIOS is an IKAROS-family zinc-finger transcription factor that plays an important role in regulatory T cell function and conventional T cell homoeostasis. HELIOS shares a conserved N-terminal DNA-binding and C-terminal dimerization domain with other IKAROS family members. Recent studies have identified germline HELIOS variants in inborn errors of immunity. Most variants are autosomal dominant, with one reported biallelic missense case. HELIOS dysfunction results in a spectrum of clinical manifestations depending on the underlying pathophysiology. Loss-of-function (LOF) variants impairing DNA binding and dimerization functions are associated with combined immunodeficiency and/or immune dysregulation (immune thrombocytopenia [ITP], autoimmune hemolytic anemia [AIHA], systemic lupus erythematosus [SLE], etc.), whereas dominant-negative variants (e.g., G153R, Exon5 duplication) are linked to syndromic presentations, including developmental abnormalities and immune dysregulation. Here, we investigated a patient born to consanguineous parents, carrying a biallelic nonsense variant (R477*) and presenting with immunodeficiency, lymphoproliferation, autoimmune cytopenias, craniofacial anomalies, sensorineural hearing loss, and developmental delay. HELIOS expression was almost absent in the patient’s regulatory T cells (Tregs), whereas the mutant protein was detectable in EBV-transformed B cells. The mutant lacked both homo- and heterodimerization due to the absence of the dimerization domain and showed reduced protein stability, suggesting that the loss of HELIOS observed in patient Tregs is likely due to decreased protein stability. Further functional analyses revealed that the mutant failed to localize to pericentromeric-heterochromatin and exhibited abnormal monomeric, rather than canonical dimeric/multimeric DNA binding, features resembling IKAROS dimerization-defective mutations.
Immunophenotyping showed that the patient exhibited an abnormal lymphocyte immunophenotype characterized by decreased Treg and naïve T cells, increased T folicular helper (Tfh) and CD8+-TEMRA cells, and reduced B cell number with low memory B cells. The patient’s parents and three siblings are R477* heterozygous carriers. While the parents are healthy, the two siblings exhibit features of immune dysregulation (celiac disease, asthma), which may or may not be associated with the variant. Consistent with previous reports in patients with LOF variants, heterozygous family members show reduced Treg and mucosal associated invariant T (MAIT) cell frequencies, while overall lymphocyte phenotypes remain largely unaffected.
This novel HELIOS-associated disease expands the understanding of pathogenic HELIOS allelic variants, their genotype–phenotype correlation, and mechanisms of disease, while highlighting their impact on lymphocyte subset development and nonimmune manifestations.
