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We previously mapped a rare form of X\u2010linked CMT, CMTX3, to a 5.7\u2010Mb interval on chromosome Xq26.3\u2010q27.1 and excluded the coding region of all known genes in the linkage interval for mutations. Whole genome sequencing subsequently identified a 78\u2010kb region of chromosome 8q24.3 that had been duplicated and inserted into the CMTX3 locus between the genes\n                    <jats:italic>HAPSTR2<\/jats:italic>\n                    and\n                    <jats:italic>SOX3<\/jats:italic>\n                    . The 78\u2010kb insertion, which contains a partial transcript of\n                    <jats:italic>ARHGAP39<\/jats:italic>\n                    , fully segregated in families with CMTX3 and was absent in neurologically normal controls. To retain the CMTX3 insertion and investigate its consequences in appropriate neuronal tissue, we generated induced pluripotent stem cells (iPSCs) from CMTX3 fibroblasts. Using bulk RNA sequencing of patient\u2010derived spinal motor neurons,\n                    <jats:italic>ARHGAP39<\/jats:italic>\n                    was deemed nonpathogenic by excluding both the formation of novel fusion transcripts and dosage effects from the partial duplication. Subsequent NanoString expression analyses of candidate genes within the CMTX3 locus, across different stages of neuronal differentiation, identified spatiotemporal dysregulation of\n                    <jats:italic>SOX3.<\/jats:italic>\n                    NanoString showed reduced\n                    <jats:italic>SOX3<\/jats:italic>\n                    expression in patient iPSCs. RNA sequencing detected\n                    <jats:italic>SOX3<\/jats:italic>\n                    downregulation in CMTX3 neuroepithelial progenitor cells, which was further confirmed by quantitative proteomics. Given the early onset and relatively rapid progression of CMTX3, these data prioritise\n                    <jats:italic>SOX3<\/jats:italic>\n                    as a leading candidate gene, consistent with its role as one of the earliest transcription factors expressed in the developing nervous system and a key regulator of neuronal fate.\n                  <\/jats:p>","DOI":"10.1155\/humu\/4225263","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:33:27Z","timestamp":1789122807000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Charcot\u2013Marie\u2013Tooth Neuropathy (CMTX3) Complex Structural Variation Causes Differential SOX3 Spatiotemporal Expression"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6138-5137","authenticated-orcid":false,"given":"Alexandra","family":"Boyling","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4527-3710","authenticated-orcid":false,"given":"Anthony N.","family":"Cutrupi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-9658","authenticated-orcid":false,"given":"Desmond","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5366-4554","authenticated-orcid":false,"given":"Ben","family":"Crossett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6242-1941","authenticated-orcid":false,"given":"Jonathan J.","family":"Danon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Harvey-Latham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9694-066X","authenticated-orcid":false,"given":"Garth A.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8323-873X","authenticated-orcid":false,"given":"Steve","family":"Vucic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-5074","authenticated-orcid":false,"given":"Marina L.","family":"Kennerson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1974.tb00638.x"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/0883073815604227"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8266101"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000247271.40782.b7"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006177"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.390"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.842860"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2024-333436"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac424"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1039\/C7CC08686E"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-66266-5"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.041541"},{"key":"e_1_2_10_13_2","unstructured":"NanoString Technologies Reference Genes for Normalization of Expression Data 2009 https:\/\/nanostring.com\/wp-content\/uploads\/TN_Normalization_of_Expression_Data.pdf."},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001138"},{"key":"e_1_2_10_15_2","doi-asserted-by":"crossref","unstructured":"NicoriciD. \u015eatalanM. 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