{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:09:30Z","timestamp":1781712570920,"version":"3.54.5"},"reference-count":21,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health","award":["ZIC HL006145"],"award-info":[{"award-number":["ZIC HL006145"]}]},{"name":"To Cure a Rose Foundation","award":["ZIC HL006145"],"award-info":[{"award-number":["ZIC HL006145"]}]},{"name":"Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health","award":["ZIC HL006145"],"award-info":[{"award-number":["ZIC HL006145"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>X chromosome inactivation (XCI) is a fundamental epigenetic process that balances X-linked gene expression between females and males by silencing one X chromosome in female cells. Variability or skewing of XCI can influence the clinical presentation of X-linked disorders. Bain type X-linked intellectual disability syndrome (MRXSB), caused by mutations in the X-linked HNRNPH2 gene, is characterized by intellectual disability, developmental delay, and neurological abnormalities. In female patients, XCI heterogeneity complicates disease modeling and therapeutic development. Induced pluripotent stem cells (iPSCs) offer a unique platform to study patient-specific disease mechanisms, but the dynamics of XCI during iPSC reprogramming, maintenance, and differentiation are not fully understood. In this study, we generated 12 iPSC clones from fibroblasts of a female MRXSB patient heterozygous for the HNRNPH2 c.340C &gt; T mutation. Four clones expressed the mutant HNRNPH2 allele and eight expressed the wild-type allele, indicating X chromosome reactivation (XCR) followed by random XCI during reprogramming. Importantly, these XCI patterns remained stable during long-term iPSC propagation and subsequent differentiation into the three germ layers and neural stem cells. Our findings provide new insights into XCI and XCR dynamics in the context of X-linked neurodevelopmental disorders and emphasize the importance of careful clone selection for accurate disease modeling using iPSC-based approaches.<\/jats:p>","DOI":"10.3390\/cells14191486","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T13:48:37Z","timestamp":1758635317000},"page":"1486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reactivation of Human X-Linked Gene and Stable X-Chromosome Inactivation Observed in Generation and Differentiation of iPSCs from a Female Patient with HNRNPH2 Mutation"],"prefix":"10.3390","volume":"14","author":[{"given":"Guibin","family":"Chen","sequence":"first","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Rodriguez-Lopez","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darawalee","family":"Wangsa","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa Madan","family":"Lomash","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Huang","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6900-6553","authenticated-orcid":false,"given":"Catherine Z.","family":"Chen","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1480-403X","authenticated-orcid":false,"suffix":"Jr.","given":"Rodney A.","family":"Bowling","sequence":"additional","affiliation":[{"name":"To Cure a Rose Foundation, Building 4000, 6101 Highland Campus Dr #2250, Austin, TX 78752, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neda","family":"Ghousifam","sequence":"additional","affiliation":[{"name":"To Cure a Rose Foundation, Building 4000, 6101 Highland Campus Dr #2250, Austin, TX 78752, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7079-506X","authenticated-orcid":false,"given":"Courtney J.","family":"Banks","sequence":"additional","affiliation":[{"name":"To Cure a Rose Foundation, Building 4000, 6101 Highland Campus Dr #2250, Austin, TX 78752, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin A.","family":"Hurd","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-0549","authenticated-orcid":false,"given":"Jizhong","family":"Zou","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-0757","authenticated-orcid":false,"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.ajhg.2016.06.028","article-title":"Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females","volume":"99","author":"Bain","year":"2016","journal-title":"Am. 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