{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:02:57Z","timestamp":1791259377057,"version":"4.1.0"},"reference-count":50,"publisher":"BMJ","issue":"11","funder":[{"name":"Office of Strategic Coordination\/Office of the NIH Director under Award","award":["U01HG007709"],"award-info":[{"award-number":["U01HG007709"]}]},{"DOI":"10.13039\/100012285","name":"BC Children\u2019s Hospital Research Institute","doi-asserted-by":"crossref","award":["F17-04161"],"award-info":[{"award-number":["F17-04161"]}],"id":[{"id":"10.13039\/100012285","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 178054"],"award-info":[{"award-number":["PJT 178054"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001245","name":"Jeffrey Modell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001245","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Providence Healthcare Research Institute Early Career Investigator award"},{"name":"Health Professional-Investigator award from Michael Smith Health Research BC"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vanier Canada Graduate Scholarship"},{"name":"The University of British Columbia Four Year Doctoral Fellowship"},{"DOI":"10.13039\/501100000233","name":"Genome British Columbia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000233","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008762","name":"Genome Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008762","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tier 1 Canada Research Chair in Pediatric Precision Health"},{"name":"Aubrey J. Tingle Professor of Pediatric Immunology"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,5,29]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Helios (encoded by <jats:italic>IKZF2<\/jats:italic>), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4<jats:sup>+<\/jats:sup> regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Genome sequencing revealed <jats:italic>de novo<\/jats:italic> heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function\u2014repressing <jats:italic>IL2<\/jats:italic> transcription activity\u2014in a dominant negative manner.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study is the first to describe dominant negative <jats:italic>IKZF2<\/jats:italic> variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-109127","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T13:20:42Z","timestamp":1686748842000},"page":"1092-1104","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Dominant negative variants in <i>IKZF2<\/i> cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay"],"prefix":"10.1136","volume":"60","author":[{"given":"Arezoo","family":"Mohajeri","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Vaseghi-Shanjani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui Xiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of British Columbia and BC Children's Hospital, Vancouver, British 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