{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:34:52Z","timestamp":1760060092000,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"TGen (Translational Genomics Research Institute, part, of City of Hope)"},{"name":"the Royal Children\u2019s Hospital Foundation"},{"name":"the Murdoch Children\u2019s Research Institute"},{"name":"The Harbig Foundation"},{"name":"Paula Fox"},{"name":"The Andrew and Geraldine Buxton Foundation"},{"name":"The Pierce Armstrong Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants. Here we demonstrate the clinical utility of epigenetic signatures in prioritizing variants of uncertain significance in genes associated with developmental delay (DD) and intellectual disability (ID). Methods: Genome sequencing was performed in a male with developmental delay. He was found to have VUSs in both PHF6 and DDB1 genes, linked with B\u00f6rjeson\u2013Forssman\u2013Lehmann syndrome (BFLS) and White\u2013Kernohan syndrome (WHIKERS), respectively. These two disorders share a similar phenotype but have distinct inheritance patterns and molecular pathogenic mechanisms. DNA methylation profiling (DNAm) of whole blood was performed using the clinically validated EpiSign assay. Results: The proband\u2019s methylation profile demonstrated a strong correlation with the BFLS methylation signature, supporting the PHF6 variant as a likely cause of his neurodevelopmental disorder. Conclusions: Epigenetic testing for disorders with distinct methylation patterns can provide diagnostic utility when a patient presents with variants of uncertain significance in genes associated with developmental delay. Epigenetic signatures can also guide genetic counselling and family planning.<\/jats:p>","DOI":"10.3390\/genes16080933","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating B\u00f6rjeson\u2013Forssman\u2013Lehmann (BFLS) and White\u2013Kernohan (WHIKERS) Syndromes"],"prefix":"10.3390","volume":"16","author":[{"given":"Keri","family":"Ramsey","sequence":"first","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Supraja","family":"Prakash","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Hospital, Phoenix, AZ 85016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-6606","authenticated-orcid":false,"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Center, London Health Sciences Center, London, ON N6A 5W9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Center, London Health Sciences Center, London, ON N6A 5W9, Canada"},{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"White","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services, Murdoch Children\u2019s Research Institute, Melbourne, VIC 3052, Australia"},{"name":"Department of Paediatrics, Univerwsity of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Naymik","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Sloan","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Bonfitto","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8868-5891","authenticated-orcid":false,"given":"Newell","family":"Belnap","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meredith","family":"Sanchez-Castillo","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3020-6005","authenticated-orcid":false,"given":"Wayne","family":"Jepsen","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7390-9918","authenticated-orcid":false,"given":"Matthew","family":"Huentelman","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-6983","authenticated-orcid":false,"given":"Saunder","family":"Bernes","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Hospital, Phoenix, AZ 85016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0658-3847","authenticated-orcid":false,"given":"Vinodh","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0612-7470","authenticated-orcid":false,"given":"Shagun","family":"Kaur","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Hospital, Phoenix, AZ 85016, USA"},{"name":"Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.ajhg.2021.03.007","article-title":"A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome","volume":"108","author":"White","year":"2021","journal-title":"Am. 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