{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T19:30:07Z","timestamp":1770838207822,"version":"3.50.1"},"reference-count":23,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["15\u2010HG\u20100130"],"award-info":[{"award-number":["15\u2010HG\u20100130"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Intellectual developmental disorder with autism and macrocephaly (IDDAM, OMIM #615032) is an autosomal dominant neurodevelopmental disorder characterized primarily by intellectual disability, autism spectrum disorder, macrocephaly, tall stature, gastrointestinal symptoms, and variable neurological manifestations. Most cases result from de novo pathogenic variants in\n                      <jats:italic>CHD8<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted genome sequencing through the Undiagnosed Diseases Network (UDN) in a female proband harboring a\n                      <jats:italic>CHD8<\/jats:italic>\n                      variant of uncertain significance (VUS), whose clinical presentation was consistent with IDDAM but included atypical features such as ptosis and hearing loss. Variant pathogenicity was further evaluated using EpiSign DNA methylation analysis and structural biology modeling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genome sequencing confirmed the\n                      <jats:italic>CHD8<\/jats:italic>\n                      variant inherited from her father, who exhibited a subtle feature, including traits consistent with attention\u2010deficit\/hyperactivity disorder. Pathogenicity was confirmed through epigenetic signature testing (EpiSign), demonstrating characteristic methylation patterns and structural biology analysis, predicting significant protein destabilization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We describe the case of IDDAM caused by a paternally inherited\n                      <jats:italic>CHD8<\/jats:italic>\n                      variant. Our findings highlight the importance of considering parental inheritance in IDDAM diagnoses and suggest epigenetic and structural biology analyses as valuable tools for reclassifying VUS when variant pathogenicity remains uncertain.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70165","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T01:04:13Z","timestamp":1766019853000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Variability and Paternal Inheritance of a\n                    <i>CHD8<\/i>\n                    Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7278-8242","authenticated-orcid":false,"given":"Yutaka","family":"Furuta","sequence":"first","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly M.","family":"Ezell","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rizwan","family":"Hamid","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joy D.","family":"Cogan","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas A.","family":"Cassini","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynette","family":"Rives","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"McMinn","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shailee","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda C.","family":"Peltier","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Layfield","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin S.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew L.","family":"Tedder","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6788-1151","authenticated-orcid":false,"given":"Raymond J.","family":"Louie","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-7483","authenticated-orcid":false,"given":"Jennifer A.","family":"Lee","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Division of Molecular Diagnostics London Health Sciences  London Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Rzasa","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Division of Molecular Diagnostics London Health Sciences  London Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Division of Molecular Diagnostics London Health Sciences  London Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"Al Mamun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science Meharry School of Applied Computational Sciences  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan H.","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher W.","family":"Moth","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharmacology, and Biomedical Informatics Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharmacology, and Biomedical Informatics Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marissa","family":"Vawter\u2010Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Neurology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola Maria","family":"Mendoza\u2010Sengco","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pediatric Rehabilitation Medicine Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer B.","family":"Holzen","sequence":"additional","affiliation":[{"name":"Tennessee Pediatrics  Hendersonville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumit","family":"Pruthi","sequence":"additional","affiliation":[{"name":"Department of Radiology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"John A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7093-8844","authenticated-orcid":false,"given":"Rory J.","family":"Tinker","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Genomics Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","unstructured":"Ab E. R. N.deJong T.Diercks et\u00a0al.2006.\u201cSolution Structures of the BRK Domains of the Human Chromo Helicase Domain 7 and 8 Reveals Structural Similarity With GYF Domain Suggesting a Role in Protein Interaction.\u201dDeposited: 2006\u201004\u201014.https:\/\/www.rcsb.org\/structure\/2CKA.","DOI":"10.2210\/pdb2cka\/pdb"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010020\u201002115\u20109"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.01.019"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.017"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1132"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398\u2010022\u201002189\u20101"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13554"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.558247"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13882"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2024.101075"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12617"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xhgg.2021.100075"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201030936\u2010x"},{"key":"e_1_2_13_15_1","first-page":"1993","volume-title":"GeneReviews[Internet]","author":"Mitchel M. W.","year":"2022"},{"key":"e_1_2_13_16_1","doi-asserted-by":"crossref","unstructured":"Moth C. W. J. H.Sheehan A. A.Mamun et\u00a0al.2024.\u201cVUStruct: A Compute Pipeline for High Throughput and Personalized Structural Biology.\u201dbioRxiv 2024.08.06.606224.https:\/\/doi.org\/10.1101\/2024.08.06.606224.","DOI":"10.1101\/2024.08.06.606224"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31749"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.6b00819"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010020\u201001096\u20104"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148\u2010019\u20100684\u20103"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.01.017"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00322\u201008"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597\u2010024\u201003327\u20108"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70165","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.70165","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:56:39Z","timestamp":1770836199000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":23,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/mgg3.70165"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70165","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70165"}}