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The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20\u201030% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, <jats:italic>KMT2D<\/jats:italic> and <jats:italic>KDM6A<\/jats:italic>. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome\u2010wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for <jats:italic>KMT2D<\/jats:italic> led to the identification of a cryptic variant in <jats:italic>KDM6A<\/jats:italic> by genome sequencing; for the other case, a DNAm signature different from KS led to the detection of another diagnosis in the KS differential, CDK13\u2010related disorder. This approach illustrates the clinical utility of DNAm signatures in the diagnostic workflow for the genome analyst or clinical geneticist\u2014especially for disorders with overlapping clinical phenotypes.<\/jats:p>","DOI":"10.1002\/ajmg.a.62650","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T07:58:20Z","timestamp":1642579100000},"page":"1368-1375","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The utility of <scp>DNA<\/scp> methylation signatures in directing genome sequencing workflow: Kabuki syndrome and <scp>CDK13<\/scp>\u2010related disorder"],"prefix":"10.1002","volume":"188","author":[{"given":"Ashish","family":"Marwaha","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Cumming School of Medicine, The University of Calgary  Calgary Alberta Canada"},{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-9945","authenticated-orcid":false,"given":"Gregory","family":"Costain","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Pediatrics University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheryl","family":"Cytrynbaum","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Molecular Genetics University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3542-8106","authenticated-orcid":false,"given":"Roberto","family":"Mendoza\u2010Londono","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Pediatrics University of Toronto  Toronto Ontario Canada"},{"name":"Department of Molecular Genetics University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0468-6663","authenticated-orcid":false,"given":"Lauren","family":"Chad","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Pediatrics University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zain","family":"Awamleh","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Chater\u2010Diehl","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanaa","family":"Choufani","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-4150","authenticated-orcid":false,"given":"Rosanna","family":"Weksberg","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Genetics and Genome Biology Program Research Institute, The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Pediatrics University of Toronto  Toronto Ontario Canada"},{"name":"Department of Molecular Genetics University of Toronto  Toronto Ontario Canada"},{"name":"Institute of Medical Sciences, University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105625"},{"key":"e_1_2_9_3_1","volume-title":"GeneReviews((R))","author":"Adam M. 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