{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T17:41:37Z","timestamp":1781804497230,"version":"3.54.5"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":152,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014607","name":"Royal Children's Hospital Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014607","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022098","name":"Mito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2009732"],"award-info":[{"award-number":["GNT2009732"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>Rett syndrome (RTT) is a rare, X\u2010linked, severe neurodevelopmental disorder, predominantly associated with pathogenic variants in the methyl\u2010CpG\u2010binding protein\u20102 (<jats:italic>MECP2<\/jats:italic>) gene, with an increasing number of atypical RTT or RTT\u2010like individuals having pathogenic variants in other genes, such as cyclin\u2010dependent kinase\u2010like 5 (<jats:italic>CDKL5<\/jats:italic>) or forkhead box G1 (<jats:italic>FOXG1<\/jats:italic>). However, ~20% of individuals with a clinical diagnosis of RTT remain genetically undiagnosed, highlighting the importance of ongoing genomic and functional studies to expand the genetic spectrum of RTT. We present a female who was born to healthy nonconsanguineous parents and presented with severe intellectual disability, macrocephaly, ataxia, absent speech, and poor eye contact. The affected individual was clinically diagnosed with atypical RTT, but genetic testing showed no pathogenic variants in <jats:italic>MECP2<\/jats:italic>, <jats:italic>CDKL5<\/jats:italic>, or <jats:italic>FOXG1.<\/jats:italic> Singleton whole genome sequencing was conducted, which identified a heterozygous stop\u2013gain variant [NM_001170629.2: c.5017C&gt;T, p.(Arg1673\u2009<jats:sup>\u2217<\/jats:sup>)], in the chromodomain\u2010helicase\u2010DNA\u2010binding protein 8 (<jats:italic>CHD8<\/jats:italic>) gene. Variant curation revealed its absence in unaffected populations, in silico predictions of pathogenicity, and an existing association with <jats:italic>intellectual developmental disorder with autism and macrocephaly<\/jats:italic> (<jats:italic>IDDAM<\/jats:italic>) (OMIM #615032). In vitro functional analyses, including Western blots, quantitative reverse transcription polymerase chain reaction (qRT\u2010PCR), and proteomic analyses, demonstrated a significant reduction of the CHD8 transcript and two CHD8 protein isoforms in the proband\u2019s skin fibroblasts relative to control fibroblasts. Additionally, proteomic analysis indicated a significant reduction of the MeCP2 protein, indicating a possible molecular link between CHD8 and MeCP2 and thus clinically between IDDAM and RTT. As the affected individual\u2019s phenotype is consistent with atypical RTT, our results suggest that <jats:italic>CHD8<\/jats:italic> could be considered in the expanding genetic spectrum of atypical RTT, which may assist the diagnosis of other <jats:italic>MECP2<\/jats:italic>\u2010negative RTT individuals.<\/jats:p>","DOI":"10.1155\/humu\/5485987","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T11:05:44Z","timestamp":1748862344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>CHD8<\/i> Variant and Rett Syndrome: Overlapping Phenotypes, Molecular Convergence, and Expanding the Genetic Spectrum"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8126-3190","authenticated-orcid":false,"given":"Elaine","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3445-3898","authenticated-orcid":false,"given":"Teresa","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-9207","authenticated-orcid":false,"given":"Tim","family":"Sikora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5752-5698","authenticated-orcid":false,"given":"Carolyn","family":"Ellaway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1808-0646","authenticated-orcid":false,"given":"Wendy A.","family":"Gold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6768-3665","authenticated-orcid":false,"given":"Nicole J.","family":"Van Bergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2048-3383","authenticated-orcid":false,"given":"David A.","family":"Stroud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-0641","authenticated-orcid":false,"given":"John","family":"Christodoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0689-2965","authenticated-orcid":false,"given":"Simranpreet","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22124"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1153252"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0006-3"},{"key":"e_1_2_12_4_2","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1086\/426462","article-title":"Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder With Infantile Spasms and Mental Retardation","volume":"75","author":"Weaving L. 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