{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T22:31:15Z","timestamp":1772145075513,"version":"3.50.1"},"reference-count":17,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Health Labour Sciences Research Grant","award":["JPMH24FC1008"],"award-info":[{"award-number":["JPMH24FC1008"]}]},{"name":"Daiwa Securities Co. Ltd.","award":["a donation from Global All Bio-Genome Equity Fund"],"award-info":[{"award-number":["a donation from Global All Bio-Genome Equity Fund"]}]},{"name":"Nikko Asset Management Co., Ltd.","award":["a donation from Global All Bio-Genome Equity Fund"],"award-info":[{"award-number":["a donation from Global All Bio-Genome Equity Fund"]}]},{"DOI":"10.13039\/501100009438","name":"National Center of Neurology and Psychiatry","doi-asserted-by":"publisher","award":["Intramural Research Grant (3-7, 6-6)"],"award-info":[{"award-number":["Intramural Research Grant (3-7, 6-6)"]}],"id":[{"id":"10.13039\/501100009438","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,10,6]]},"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:p>Pathogenic variants of WD repeat domain 45 (<jats:italic>WDR45<\/jats:italic>) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of <jats:italic>WDR45<\/jats:italic> using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, <jats:italic>WDR45<\/jats:italic> variants accounted for 12% (6\/51) of the females with developmental delay, suggesting that <jats:italic>WDR45<\/jats:italic> is a major gene in females with developmental delay. Pathogenic variants of <jats:italic>WDR45<\/jats:italic> result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.<\/jats:p>","DOI":"10.1136\/jmg-2024-110068","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T13:20:35Z","timestamp":1730121635000},"page":"1119-1122","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["<i>WDR45<\/i> variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2584-7921","authenticated-orcid":false,"given":"Chihiro","family":"Abe-Hatano","sequence":"first","affiliation":[{"name":"Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7391-0799","authenticated-orcid":false,"given":"Ken","family":"Inoue","sequence":"additional","affiliation":[{"name":"Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan"},{"name":"Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eri","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0666-1224","authenticated-orcid":false,"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[{"name":"Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2426-9739","authenticated-orcid":false,"given":"Yu-ichi","family":"Goto","sequence":"additional","affiliation":[{"name":"Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"2025101712263073000_61.12.1119.1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1899669"},{"key":"2025101712263073000_61.12.1119.2","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000000227","article-title":"WDR45 mutations may cause a MECP2 mutation-negative Rett 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