{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:59:15Z","timestamp":1777323555122,"version":"3.51.4"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"publisher","award":["887172"],"award-info":[{"award-number":["887172"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ontario Brain Institute (Province of Ontario Neurodevelopmental Disorders (POND) network","award":["IDS11-02"],"award-info":[{"award-number":["IDS11-02"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-178315"],"award-info":[{"award-number":["PJT-178315"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11\u2019s role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina\u2019s Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n\u2009=\u200914) from typically developing controls (n\u2009=\u200928). This DNAm signature\u00a0was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.<\/jats:p>","DOI":"10.1093\/hmg\/ddac289","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T08:24:38Z","timestamp":1669364678000},"page":"1429-1438","source":"Crossref","is-referenced-by-count":17,"title":["<i>ANKRD11<\/i> pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome"],"prefix":"10.1093","volume":"32","author":[{"given":"Zain","family":"Awamleh","sequence":"first","affiliation":[{"name":"The Hospital for Sick Children Genetics and Genome Biology Program, Research Institute, , Toronto, ON M5G 1X8 , Canada"}]},{"given":"Sanaa","family":"Choufani","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children Genetics and Genome Biology Program, Research Institute, , Toronto, ON M5G 1X8 , Canada"}]},{"given":"Cheryl","family":"Cytrynbaum","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children Division of Clinical and Metabolic Genetics, , Toronto, ON M5G 1X8 , Canada"}]},{"given":"Fowzan\u00a0S","family":"Alkuraya","sequence":"additional","affiliation":[{"name":"King Faisal Specialist Hospital and Research Center Department of Translational Genomics, Center for Genomic Medicine, , Riyadh , Saudi Arabia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8326-1999","authenticated-orcid":false,"given":"Stephen","family":"Scherer","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children Genetics and Genome Biology Program, Research Institute, , Toronto, ON M5G 1X8 , Canada"},{"name":"University of Toronto Department of Molecular Genetics, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto Institute of Medical Sciences, , Toronto, ON M5S 1A8 , Canada"}]},{"given":"Sofia","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE Medical Genetics Unit, , Coimbra , Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil Familial Risk Clinic, , Lisbon , Portugal"}]},{"given":"Catarina","family":"Rosas","sequence":"additional","affiliation":[{"name":"Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE Medical Genetics Unit, , Coimbra , Portugal"}]},{"given":"Pedro","family":"Louro","sequence":"additional","affiliation":[{"name":"Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE Medical Genetics Unit, , Coimbra , Portugal"}]},{"given":"Patricia","family":"Dias","sequence":"additional","affiliation":[{"name":"Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, EPE Servi\u00e7o de Gen\u00e9tica M\u00e9dica, Departamento de Pediatria, , Lisbon , Portugal"}]},{"given":"Mariana\u00a0Tom\u00e1sio","family":"Neves","sequence":"additional","affiliation":[{"name":"Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, EPE Servi\u00e7o de Gen\u00e9tica M\u00e9dica, Departamento de Pediatria, , Lisbon , Portugal"}]},{"given":"S\u00e9rgio B","family":"Sousa","sequence":"additional","affiliation":[{"name":"Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE Medical Genetics Unit, , Coimbra , Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-4150","authenticated-orcid":false,"given":"Rosanna","family":"Weksberg","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children Genetics and Genome Biology Program, Research Institute, , Toronto, ON M5G 1X8 , Canada"},{"name":"The Hospital for Sick Children Division of Clinical and Metabolic Genetics, , Toronto, ON M5G 1X8 , Canada"},{"name":"University of Toronto Department of Molecular Genetics, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto Institute of Medical Sciences, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto Department of Paediatrics, , Toronto, ON M5S 1A8 , Canada"}]}],"member":"286","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"2023042013345484800_ref1","doi-asserted-by":"crossref","first-page":"33799","DOI":"10.1074\/jbc.M403997200","article-title":"Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators","volume":"279","author":"Zhang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2023042013345484800_ref2","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.bbrc.2007.05.017","article-title":"Characterization of transcriptional regulatory domains of ankyrin repeat cofactor-1","volume":"358","author":"Zhang","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023042013345484800_ref3","first-page":"7","article-title":"The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies","volume":"11","author":"Herrmann","year":"1975","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"2023042013345484800_ref4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ajhg.2011.06.007","article-title":"Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia","volume":"89","author":"Sirmaci","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2023042013345484800_ref5","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1002\/ajmg.a.37842","article-title":"Clinical and genetic aspects of KBG syndrome","volume":"170","author":"Low","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"2023042013345484800_ref6","article-title":"Adam MP, Ardinger H., Pagon RA (ed.). KBG Syndrome. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022","author":"Morel Swols","year":"2018","journal-title":"GeneReviews"},{"key":"2023042013345484800_ref7","doi-asserted-by":"crossref","DOI":"10.3390\/jpm12030407","article-title":"Genetic and phenotypic Spectrum of KBG syndrome: a report of 13 new Chinese cases and a review of the literature","volume":"12","author":"Gao","year":"2022","journal-title":"J. Pers. 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