{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:10:11Z","timestamp":1778479811742,"version":"3.51.4"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1362\/17"],"award-info":[{"award-number":["1362\/17"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["817\/23"],"award-info":[{"award-number":["817\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>ZBTB24 is a member of a protein family containing a Broad-Complex, Tramtrack, and Bric a Brac (BTB) domain, which functions in protein\u2013protein interactions. ZBTB24, a transcription factor, binds its DNA targets through its C-terminal zinc finger (ZF) domain. Biallelic ZBTB24 pathogenic variants lead to the rare autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies type 2 (ICF2) syndrome. The majority of ICF2 patients carry biallelic loss-of-function variants in ZBTB24. The remaining patients harbor missense variants in the ZF domain that compromise the ability of ZBTB24 to transcriptionally activate CDCA7, the gene responsible for ICF subtype 3 syndrome. Although an ICF2 patient with compound heterozygous pathogenic variants, including a missense variant (p.Ser59Gly) in the BTB domain, has been reported, no ICF2 patients with biallelic missense variants in any ZBTB24 domains other than the zinc finger domain have been described. Similar to all subtypes of ICF syndrome, ZBTB24 pathogenic variants lead to significant DNA hypomethylation throughout the genome. Here we describe a patient with severe infections initiating during her first year of life, significant developmental delay and an abnormal facial shape, who carries a homozygous p.Val43Leu substitution in the BTB domain of ZBTB24. The patient\u2019s peripheral blood cells demonstrate whole genome DNA hypomethylation with patterns identical to those found in verified ICF2 patients. Both the p.Val43Leu and p.Ser59Gly variants cause significant ZBTB24 protein instability. Thus, we demonstrate that pathogenic missense variants in the BTB domain of ZBTB24 can functionally act as loss-of-function variants that result in ICF2 syndrome.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf182","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T12:37:53Z","timestamp":1763987873000},"source":"Crossref","is-referenced-by-count":0,"title":["Missense substitutions in the BTB domain of ZBTB24 can lead to protein instability and cause ICF2 syndrome"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-8901","authenticated-orcid":false,"given":"Or","family":"Givol","sequence":"first","affiliation":[{"name":"Pediatric Department, Hillel-Yaffe Medical Center, Hashalom Street, Hedera \u00a0 38100 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6560-0544","authenticated-orcid":false,"given":"Ido S","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Genetics and Developmental Biology, B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Cecere","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Institute of Genetics and Biophysics \"Adriano Buzzati-Traverso\", Consiglio Nazionale delle Ricerche (CNR) , Via Pietro Castellino 111, Naples 80131 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liran","family":"Giladi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Developmental Biology, B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8238-9169","authenticated-orcid":false,"given":"Noa","family":"Dotan-Glick","sequence":"additional","affiliation":[{"name":"Department of Genetics and Developmental Biology, B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Revital","family":"Shemer","sequence":"additional","affiliation":[{"name":"Department of Genetics and Developmental Biology, B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atar","family":"Lev","sequence":"additional","affiliation":[{"name":"Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Ramat-Gan 5262000 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amos J","family":"Simon","sequence":"additional","affiliation":[{"name":"Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Ramat-Gan 5262000 ,","place":["Israel"]},{"name":"Hemato-Immunology Unit, Hematology Lab and Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan, 5262000 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nivin","family":"Moustafa-Hawash","sequence":"additional","affiliation":[{"name":"The Genetics Institute, Rambam Health Care Campus , 8 HaAliya HaShniya Street, Haifa 35254 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Itzkovich","sequence":"additional","affiliation":[{"name":"The Clinical Research Institute, Rambam Health Care Campus , 8 HaAliya HaShniya Street, Haifa 352540 ,","place":["Israel"]},{"name":"B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vered","family":"Schichter-Konfino","sequence":"additional","affiliation":[{"name":"Pediatric Department, Hillel-Yaffe Medical Center, Hashalom Street, Hedera \u00a0 38100 ,","place":["Israel"]},{"name":"Allergy and Immunology Unit, Hillel-Yaffe Medical Center, Hashalom Street, Hedera \u00a0 38100 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raz","family":"Somech","sequence":"additional","affiliation":[{"name":"Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center , Tel Hashomer, Ramat-Gan 5262000 ,","place":["Israel"]},{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University , 35 Klatzkin Street, Tel Aviv 69978 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Weiss","sequence":"additional","affiliation":[{"name":"The Genetics Institute, Rambam Health Care Campus , 8 HaAliya HaShniya Street, Haifa 35254 ,","place":["Israel"]},{"name":"B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron Street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Kornitzer","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, B. Rappaport Faculty of Medicine, Technion-I.I.T. , 1 Efron street, Haifa 31096 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9629-3818","authenticated-orcid":false,"given":"Motoko","family":"Unoki","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of International Health, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rosaria","family":"Matarazzo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Institute of Genetics and Biophysics \"Adriano Buzzati-Traverso\", Consiglio Nazionale delle Ricerche (CNR) , Via Pietro Castellino 111, Naples 80131 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5759-9948","authenticated-orcid":false,"given":"Sara","family":"Selig","sequence":"additional","affiliation":[{"name":"Department of Genetics and Developmental Biology, B. 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