{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:34:40Z","timestamp":1789835680428,"version":"4.0.1"},"reference-count":17,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY027421"],"award-info":[{"award-number":["R01EY027421"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["X01HL132377"],"award-info":[{"award-number":["X01HL132377"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with <jats:italic>ZNF462<\/jats:italic> loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in <jats:italic>ZNF46<\/jats:italic>2. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow\/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with <jats:italic>ZNF462<\/jats:italic> loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of <jats:italic>ZNF462<\/jats:italic> that has distinct clinical characteristics and facial features.<\/jats:p>","DOI":"10.1002\/ajmg.a.61306","type":"journal-article","created":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T14:10:08Z","timestamp":1564495808000},"page":"2075-2082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Phenotype delineation of <i>ZNF462<\/i> related syndrome"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-0875","authenticated-orcid":false,"given":"Paul","family":"Kruszka","sequence":"first","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy","family":"Hu","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungkook","family":"Hong","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Signer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics David Geffen School of Medicine, University of California  Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Cogn\u00e9","sequence":"additional","affiliation":[{"name":"Service de g\u00e9n\u00e9tique m\u00e9dicale, H\u00f4tel\u2010Dieu  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betrand","family":"Isidor","sequence":"additional","affiliation":[{"name":"Service de g\u00e9n\u00e9tique m\u00e9dicale, H\u00f4tel\u2010Dieu  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Mazzola","sequence":"additional","affiliation":[{"name":"Division of Human Genetics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques C.","family":"Giltay","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen L. I.","family":"van Gassen","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleina M.","family":"England","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Pais","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics Broad Institute of MIT and Harvard  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte W.","family":"Ockeloen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A.","family":"Sanchez\u2010Lara","sequence":"additional","affiliation":[{"name":"Keck School of Medicine University of Southern California  Los Angeles California"},{"name":"Department of Pediatrics David Geffen School of Medicine, University of California  Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Kinning","sequence":"additional","affiliation":[{"name":"West of Scotland Genetics Service Queen Elizabeth Hospitals  Glasgow Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius J.","family":"Adams","sequence":"additional","affiliation":[{"name":"Personalized Genomic Medicine and Pediatric Genetics, Atlantic Health System  Morristown New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Treat","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics, Indiana University School of Medicine  Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfredo","family":"Torres\u2010Martinez","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics, Indiana University School of Medicine  Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0174-3562","authenticated-orcid":false,"given":"Maria F.","family":"Bedeschi","sequence":"additional","affiliation":[{"name":"Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Medica ASST Papa Giovanni XXIII  Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Blaney","sequence":"additional","affiliation":[{"name":"Genetics, Vaccine Preventable Diseases, and Sexual Health, Algoma Public Health  Sault Ste. Marie Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Bell","sequence":"additional","affiliation":[{"name":"Keck School of Medicine University of Southern California  Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiong Y.","family":"Tan","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute  Melbourne Victoria Australia"},{"name":"Department of Paediatrics University of Melbourne  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Ange","family":"Delrue","sequence":"additional","affiliation":[{"name":"D\u00e9partement de p\u00e9diatrie, Service de g\u00e9n\u00e9tique m\u00e9dicale, Centre Hospitalier Universitaire Ste\u2010Justine Universit\u00e9 de Montr\u00e9al  Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda J.","family":"Barry","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics Broad Institute of MIT and Harvard  Cambridge Massachusetts"},{"name":"Howard Hughes Medical Institute  Chevy Chase Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Engle","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics Broad Institute of MIT and Harvard  Cambridge Massachusetts"},{"name":"Howard Hughes Medical Institute  Chevy Chase Maryland"},{"name":"Department of Ophthalmology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Savage","sequence":"additional","affiliation":[{"name":"FDNA, Inc.  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Fleischer","sequence":"additional","affiliation":[{"name":"FDNA, Inc.  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6776-6949","authenticated-orcid":false,"given":"Julian A.","family":"Martinez\u2010Agosto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics David Geffen School of Medicine, University of California  Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-8052","authenticated-orcid":false,"given":"Kym","family":"Boycott","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine H.","family":"Zackai","sequence":"additional","affiliation":[{"name":"Division of Human Genetics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7719-6545","authenticated-orcid":false,"given":"Maximilian","family":"Muenke","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/nucl.2.5.17707"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2932"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modgep.2006.11.009"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2018.02.002"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.026"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0279-0"},{"key":"e_1_2_7_8_1","first-page":"531210","article-title":"Variation across 141,456 human exomes and genomes reveals the spectrum of loss\u2010of\u2010function intolerance across human protein\u2010coding genes","author":"Karczewski K. J.","year":"2019","journal-title":"BioRxiv"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.12.005"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2010.02.024"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/8.2.85"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200995"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.172"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.017"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mcd.0000072161.33788.56"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12339"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.86"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.61306","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.61306","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.61306","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T12:52:51Z","timestamp":1694091171000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.61306"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,30]]},"references-count":17,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1002\/ajmg.a.61306"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.61306","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,30]]},"assertion":[{"value":"2019-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}