{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T01:07:09Z","timestamp":1775783229614,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US NINDS","award":["K08NS117891-01"],"award-info":[{"award-number":["K08NS117891-01"]}]},{"name":"Stichting 12q"},{"name":"Wilhelmina Children\u2019s Hospital Research Fund","award":["WKZ onderzoeksfonds 2020-2021"],"award-info":[{"award-number":["WKZ onderzoeksfonds 2020-2021"]}]},{"DOI":"10.13039\/501100003246","name":"Netherlands Organisation for Scientific Research","doi-asserted-by":"publisher","award":["09150172110002"],"award-info":[{"award-number":["09150172110002"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants\u2019 effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf082","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:39:51Z","timestamp":1748306391000},"page":"1353-1367","source":"Crossref","is-referenced-by-count":3,"title":["KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome"],"prefix":"10.1093","volume":"34","author":[{"given":"Amber S E","family":"van Oirsouw","sequence":"first","affiliation":[{"name":"Graduate School of Life Sciences, Utrecht University , Heidelberglaan 8, 3584 CS Utrecht ,","place":["The Netherlands"]},{"name":"UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, Utrecht 3584 CX ,","place":["The Netherlands"]},{"name":"Department of Genetics, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, Utrecht 3584 CX ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A","family":"Hadders","sequence":"additional","affiliation":[{"name":"Oncode Institute and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University , Universiteitsweg 100, Utrecht 3584 CG ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martijn","family":"Koetsier","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, Utrecht 3584 CX ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith D J","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht, Utrecht University , Heidelberglaan 100, Utrecht 3584 CX ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nurit","family":"Assia Batzir","sequence":"additional","affiliation":[{"name":"Pediatric Genetics Unit, Schneider Children's Medical Centerl , 14 Kaplan St., Petah Tikva 4920235 ,","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tahsin Stefan","family":"Barakat","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center , Dr. Molewaterplein 50, Rotterdam 3000 CA ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Baralle","sequence":"additional","affiliation":[{"name":"Human Development and Health, Faculty of Medicine, University of Southampton , Southampton General Hospital, Tremona Road, Southampton SO16 6YD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adelyn","family":"Beil","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, Metabolism, and Genomic Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, MI 48109 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-No\u00eblle","family":"Bonnet-Dupeyron","sequence":"additional","affiliation":[{"name":"Consultations de G\u00e9n\u00e9tique, Centre Hospitalier de Valence , 179 Bd Mar\u00e9chal Juin, Valence 26000 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip M","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children's Hospital , 300 Longwood Ave., Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjan","family":"Bouman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC University Medical Center , Dr. Molewaterplein 50, Rotterdam 3000 CA ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deanna Alexis","family":"Carere","sequence":"additional","affiliation":[{"name":"GeneDx, LLC , 207 Perry Parkway, Gaithersburg, MD 20877 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Cogne","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, Centre Hospitalier Universitaire de Nantes , Service de G\u00e9n\u00e9tique m\u00e9dicale 1, place Alexis Ricordeau, 44093 Nantes ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie","family":"Dunnington","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children\u2019s Memorial Hermann Hospital , 6431 Fannin Street, MSB 3144B, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura S","family":"Farach","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children\u2019s Memorial Hermann Hospital , 6431 Fannin Street, MSB 3144B, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casie A","family":"Genetti","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children's Hospital , 300 Longwood Ave., Boston, MA 02115 ,","place":["United States"]},{"name":"Manton Center for Orphan Disease Research, Boston Children's Hospital , 300 Longwood Ave., Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Isidor","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, Centre Hospitalier Universitaire de Nantes , Service de G\u00e9n\u00e9tique m\u00e9dicale 1, place Alexis Ricordeau, 44093 Nantes ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Januel","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hospices Civils de Lyon , 3 Quai des C\u00e9lestins, Lyon 69002 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aakash","family":"Joshi","sequence":"additional","affiliation":[{"name":"St. George\u2019s University of London & St. George\u2019s University Hospitals NHS Foundation Trust , Blackshaw Road, Tooting, London SW17 0QT ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayana","family":"Lahiri","sequence":"additional","affiliation":[{"name":"St. George\u2019s University of London & St. George\u2019s University Hospitals NHS Foundation Trust , Blackshaw Road, Tooting, London SW17 0QT ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristen N","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, Metabolism, and Genomic Medicine, University of Michigan , 1500 E. 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