Abnormal SCID Newborn Screening and Spontaneous Recovery Associated with a Novel Haploinsufficiency IKZF1 Mutation



IKAROS, encoded by IKZF1, is a member of the IKAROS family of zinc-finger transcription factors playing critical roles in lymphocyte development, differentiation, and tumor suppression. Several studies demonstrated that IKZF1 mutations affecting DNA binding or homo-/hetero-dimerization are mostly associated with common variable immunodeficiency, combined immunodeficiency, or hematologic manifestations. Herein we report a likely de novo, nonsense IKZF1 mutation (p.C182*) in a baby with low T cell receptor excision circles (TREC) identified by newborn screening testing for severe combined immunodeficiency. The patient also presented a profound B cell deficiency at birth.


Genetic, functional, immunologic, and clinical outcome data associated with this patient and her mutation were evaluated.


Mutant p.C182* was detected in the cytoplasm of the patient’s primary cells, in contrast to wild type (WT) IKAROS protein, only detected in the nucleus. Functional in vitro assessments revealed that p.C182* was less stable than WT IKAROS protein and failed to bind to its target DNA binding sequence and dimerize with WT IKAROS protein, resulting in impaired pericentromeric targeting and transcriptional repression by means of haploinsufficiency. During follow-up, while a spontaneous recovery of TREC and T cells was observed, B cells improved but not to sustained normal ranges.


Patients with IKAROS-associated diseases can present with SCID-like TREC values through newborn screening testing. IKZF1 mutations should be added to the low TREC differential, although spontaneous recovery has to be considered.

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Common variable immunodeficiency


Combined immunodeficiency


T cell receptor excision circles


Pericentromeric heterochromatin


Severe combined immunodeficiency


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We thank Julie Niemela (NIH) for her contribution performing Sanger sequencing. The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. We would like to thank the patient and her family for participating in this research.


These studies were supported by grant U19HD077693 from NICHD and NHGRI and gifts from the Liguori Family, John Motter and Effie Simanikas, Ernest and Evelyn Rady, and Rady Children’s Hospital, San Diego; and the Intramural Research Program, NIH Clinical Center, US National Institutes of Health (NIH).

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NJG, DD, and CC diagnosed the patient, collected biologic and clinical data, and wrote the first draft. MT and MW performed WGS and analyzed data. HSK and SDR designed the research project and wrote the manuscript. HSK performed the experiments and analyzed the data with SDR.

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Correspondence to Sergio D. Rosenzweig.

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All patients or their guardians provided informed consent in accordance with the Declaration of Helsinki under institutional review board−approved protocols of the National Institute of Allergy and Infectious Diseases, NIH, and Western IRB (Pr #:20171726); ClinicalTrials.gov Identifier: NCT03385876.

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Kuehn, H.S., Gloude, N.J., Dimmock, D. et al. Abnormal SCID Newborn Screening and Spontaneous Recovery Associated with a Novel Haploinsufficiency IKZF1 Mutation. J Clin Immunol (2021). https://doi.org/10.1007/s10875-021-01035-1

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  • TREC
  • T cells
  • B cells
  • lymphopenia
  • CVID
  • CID
  • NBS