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

Michael S Kobor, Frederick K Kozak, Sara Mostafavi, Erika Henkelman, Connie L Yang, Jessica Halparin, Linlea Armstrong, Ronak Rahmanian, Gui Xiang Yang, Jana Gillies, Leandro B R Silva, Arezoo Mohajeri, Douglas Morrison, Stuart E Turvey, Maryam Vaseghi-Shanjani, Audi Setiadi, Areesha Salman, Susan Lin, Henry Y Lu, Maggie P Fu, Mehul Sharma, Megan K Levings, Avery J Lam, Clara van Karnebeek, Wingfield Rehmus, Mark Chilvers, Kyla J Hildebrand, Catherine M Biggs

Journal: Journal of clinical immunology 2025;45(1):89

PMID: 40295428

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Abstract

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

Address: Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.; BC Children's Hospital Research Institute, Vancouver, BC, Canada.; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.; Genome Science and Technology Program, Faculty of Science, The University of British Columbia, Vancouver, BC, Canada.; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada.; Division of Otolaryngology - Head & Neck Surgery, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Division of Hematology, Oncology & Bone Marrow Transplant, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Division of Respiratory Medicine, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Division of Plastic Surgery, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Division of Dermatology, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Department of Pathology and Laboratory Medicine, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.; Department of Statistics, The University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Division of Immunology, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada.; BC Children's Hospital Research Institute, Vancouver, BC, Canada.; Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.; School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.; Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada. [email protected].; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada. [email protected].; Division of Immunology, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada. [email protected].

DOI: 10.1007/s10875-025-01882-2