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M\u00f8ller og Hustru Chastine Mc-Kinney M\u00f8llers Fond til almene Formaal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005747","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF15OC0016474"],"award-info":[{"award-number":["NNF15OC0016474"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Sex Differ"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>46,XX testicular disorder\/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene (<jats:italic>SRY)<\/jats:italic> has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (<jats:italic>n<\/jats:italic>\u2009=\u200911), male controls (46,XY; variable cohort sizes) and female controls (46,XX; variable cohort sizes), in addition to RNA sequencing and DNA methylation analysis on blood samples from males with Klinefelter syndrome (47,XXY, <jats:italic>n<\/jats:italic>\u2009=\u200922). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (<jats:italic>n<\/jats:italic>\u2009=\u200910).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (<jats:italic>n<\/jats:italic>\u2009=\u20091), (2) with short Yp arms (breakpoint at 2.7\u20132.8\u00a0Mb, <jats:italic>n<\/jats:italic>\u2009=\u20092), (3) with medium Yp arms (breakpoint at 7.3\u00a0Mb, <jats:italic>n<\/jats:italic>\u2009=\u20091), and (4) with long Yp arms (<jats:italic>n<\/jats:italic>\u2009=\u20097), including deletions of <jats:italic>AMELY<\/jats:italic>,<jats:italic> TBLY1<\/jats:italic> and in some cases <jats:italic>PRKY<\/jats:italic>. We also identified variable expression of the X-Y homologues <jats:italic>PRKY<\/jats:italic> and <jats:italic>PRKX<\/jats:italic>. The Y-chromosomal transcriptome and methylome reflected the Y chromosome segment lengths, while changes to autosomal and X-chromosomal regions indicated global effects. Furthermore, transcriptional changes tentatively correlated with phenotypic traits of 46,XX DSD, including reduced height, lean mass and testicular size.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This study refines our understanding of the genetic composition in 46,XX DSD, describing the translocated Y chromosome segment in more detail than previously and linking variability herein to genome-wide changes in the transcriptome and methylome.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13293-024-00654-8","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T12:02:07Z","timestamp":1728388927000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Integration of long-read sequencing, DNA methylation and gene expression reveals heterogeneity in Y chromosome segment lengths in phenotypic males with 46,XX testicular disorder\/difference of sex development"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-1342","authenticated-orcid":false,"given":"Agnethe","family":"Berglund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1017-7702","authenticated-orcid":false,"given":"Emma B.","family":"Johannsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-4901","authenticated-orcid":false,"given":"Anne","family":"Skakkeb\u00e6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1130-3659","authenticated-orcid":false,"given":"Simon","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7790-6631","authenticated-orcid":false,"given":"Julia","family":"Rohayem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-2756","authenticated-orcid":false,"given":"Sandra","family":"Laurentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4624-6973","authenticated-orcid":false,"given":"Arne","family":"H\u00f8rlyck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1401-6527","authenticated-orcid":false,"given":"Simon O.","family":"Drue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6033-8521","authenticated-orcid":false,"given":"Ebbe Norskov","family":"Bak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5383-5501","authenticated-orcid":false,"given":"Jens","family":"Fedder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2745-9965","authenticated-orcid":false,"given":"Frank","family":"T\u00fcttelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-8138","authenticated-orcid":false,"given":"J\u00f6rg","family":"Gromoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-0000","authenticated-orcid":false,"given":"Jesper","family":"Just","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-1720","authenticated-orcid":false,"given":"Claus H.","family":"Gravholt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"issue":"8","key":"654_CR1","first-page":"1751","volume":"32","author":"A Berglund","year":"2017","unstructured":"Berglund A, Johannsen TH, Stochholm K, Aksglaede L, Fedder J, Viuff MH, et al. 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The study was notified to the Danish Data Protection Agency and to the Legal Department of Central Denmark Region (1-16-02-51-18) and approved by the ethical committee of Central Denmark Region (1-10-72-25-18). The data on Klinefelter syndrome was approved by The Danish Data Protection Agency and the local ethics committee (Region Midtjylland, Denmark number M-20080238). This research has been registered at ClinicalTrials.gov (Clinical trial NCT00999310). The data on 46,XX female controls stems from a study on Turner syndrome that has been approved by the ethical committee of Central Denmark Region (reference number M20110235).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"77"}}