A Germline Heterozygous Dominant Negative IKZF2 Variant Causing Syndromic Primary Immune Regulatory Disorder and ICHAD

• DOI: 10.1007/s10875-025-01882-2
• Publication Date: 2025-04-28T21:42:01Z
• Authors: Henry Y. Lu; Maryam Vaseghi-Sh...; Avery J. Lam; Mehul Sharma; Arezoo Mohajeri; Leandro B. R. Silva; Jana Gillies; Gui Xiang Yang; Susan Lin; Maggie P. Fu; Areesha Salman; Ronak Rahmanian; Linlea Armstrong; Jessica Halparin; Connie L. Yang; Mark Chilvers; Erika Henkelman; Wingfield Rehmus; Douglas Morrison; Audi Setiadi; Sara Mostafavi; Michael S. Kobor; Frederick K. Kozak; Catherine M. Biggs; Clara van Karnebeek; Kyla J. Hildebrand; ; Megan K. Levings; Stuart E. Turvey
• Keywords: Immune Dysregulation; Regulatory T cell

Abstract Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity atopy. Studying these disorders reveals important molecular cellular factors regulate human homeostasis identifies potential precision medicine targets. Here, we provide a detailed immunological assessment pediatric patient with recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) atopic dermatitis. carried de novo germline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant IKAROS family zinc finger 2 ( IKZF2 ), which encodes HELIOS. This led reduced HELIOS protein expression dominant interference wild-type HELIOS-mediated repression IL2 promoter. Multi-parameter flow cytometry analyses peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation function, increased CD8 + T activation cytokine secretion. Strikingly, CD4 were hyperactive, produced elevated levels nearly all helper (T H ) cytokines, readily proliferated response stimulation. Patient regulatory (Tregs) developed normally but aberrantly high many cytokines. Single-cell RNA sequencing largely normal Tregs (albeit mostly memory), naïve more enriched genes related activation, proliferation, metabolism, differentiation. work describes phenotype one first reported cases negative deficiency, expands our understanding pathogenesis AIHA on single level, provides valuable insights into function variety lymphocyte subsets.