{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:44:36Z","timestamp":1793133876066,"version":"4.5.0"},"reference-count":130,"publisher":"Oxford University Press (OUP)","issue":"R2","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM1273727"],"award-info":[{"award-number":["GM1273727"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HG011586"],"award-info":[{"award-number":["HG011586"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM131745"],"award-info":[{"award-number":["GM131745"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The gene content of the X and Y chromosomes has dramatically diverged during evolution. The ensuing dosage imbalance within the genome of males and females has led to unique chromosome-wide regulatory mechanisms with significant and sex-specific impacts on X-linked gene expression. X inactivation or silencing of most genes on one X chromosome chosen at random in females profoundly affects the manifestation of X-linked diseases, as males inherit a single maternal allele, while females express maternal and paternal alleles in a mosaic manner. An additional complication is the existence of genes that escape X inactivation and thus are ubiquitously expressed from both alleles in females. The mosaic nature of X-linked gene expression and the potential for escape can vary between individuals, tissues, cell types and stages of life. Our understanding of the specialized nature of X-linked genes and of the multilayer epigenetic regulation that influence their expression throughout the organism has been helped by molecular studies conducted by tissue-specific and single-cell-specific approaches. In turn, the definition of molecular events that control X silencing has helped develop new approaches for the treatment of some X-linked disorders. This review focuses on the peculiarities of the X chromosome genetic content and epigenetic regulation in shaping the manifestation of congenital and acquired X-linked disorders in a sex-specific manner.<\/jats:p>","DOI":"10.1093\/hmg\/ddab221","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T19:12:21Z","timestamp":1628277141000},"page":"R285-R295","source":"Crossref","is-referenced-by-count":31,"title":["X-factors in human disease: impact of gene content and dosage regulation"],"prefix":"10.1093","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-8092","authenticated-orcid":false,"given":"He","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxian","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M","family":"Disteche","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA"},{"name":"Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"2021100513225405800_ref1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)31561-0","article-title":"Sex and gender: modifiers of health, disease, and medicine","volume":"396","author":"Mauvais-Jarvis","year":"2020","journal-title":"Lancet"},{"key":"2021100513225405800_ref2","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41577-020-0348-8","article-title":"Considering how biological sex impacts immune responses and COVID-19 outcomes","volume":"20","author":"Scully","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"2021100513225405800_ref3","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/B978-0-12-800149-3.00005-6","article-title":"Genetics of Alzheimer's disease","volume":"87","author":"Chouraki","year":"2014","journal-title":"Adv. Genet."},{"key":"2021100513225405800_ref4","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41467-019-08475-9","article-title":"Population-wide analysis of differences in disease progression patterns in men and women","volume":"10","author":"Westergaard","year":"2019","journal-title":"Nat. Commun."},{"key":"2021100513225405800_ref5","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/ng.126","article-title":"The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression","volume":"40","author":"Mueller","year":"2008","journal-title":"Nat. Genet."},{"key":"2021100513225405800_ref6","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/andr.12686","article-title":"Clinical and molecular characterization of Y microdeletions and X-linked CNV67 implications in male fertility: a 20-year experience","volume":"8","author":"Pinho","year":"2020","journal-title":"Andrology"},{"key":"2021100513225405800_ref7","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/nature09172","article-title":"Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition","volume":"466","author":"Bellott","year":"2010","journal-title":"Nature"},{"key":"2021100513225405800_ref8","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0168-9525(01)02446-5","article-title":"A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution?","volume":"17","author":"Zechner","year":"2001","journal-title":"Trends Genet."},{"key":"2021100513225405800_ref9","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2008194118","article-title":"Darwin, sexual selection, and the brain","volume":"118","author":"Ryan","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref10","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.brainres.2006.08.053","article-title":"High expression of the mammalian X chromosome in brain","volume":"1126","author":"Nguyen","year":"2006","journal-title":"Brain Res."},{"key":"2021100513225405800_ref11","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neubiorev.2020.10.024","article-title":"X-chromosome regulation and sex differences in brain anatomy","volume":"120","author":"Raznahan","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"2021100513225405800_ref12","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1002\/ajmg.a.38710","article-title":"X-linked intellectual disability update 2017","volume":"176","author":"Neri","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"2021100513225405800_ref13","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1038\/s41436-020-0779-4","article-title":"X-linked diseases: susceptible females","volume":"22","author":"Migeon","year":"2020","journal-title":"Genet. Med."},{"key":"2021100513225405800_ref14","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/190372a0","article-title":"Gene action in the X-chromosome of the mouse (Mus musculus L.)","volume":"190","author":"LYON","year":"1961","journal-title":"Nature"},{"key":"2021100513225405800_ref15","doi-asserted-by":"crossref","first-page":"1012\u20131026","DOI":"10.1016\/j.cell.2016.03.023","article-title":"Single-cell RNA-Seq reveals lineage and X chromosome dynamics in human preimplantation embryos","volume":"165","author":"Petropoulos","year":"2016","journal-title":"Cell"},{"key":"2021100513225405800_ref16","doi-asserted-by":"crossref","DOI":"10.1242\/dev.183095","article-title":"X chromosome inactivation in human development","volume":"147","author":"Patrat","year":"2020","journal-title":"Development"},{"key":"2021100513225405800_ref17","doi-asserted-by":"crossref","first-page":"10794","DOI":"10.1038\/s41598-017-11044-z","article-title":"Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing","volume":"7","author":"Moreira de Mello","year":"2017","journal-title":"Sci. Rep."},{"key":"2021100513225405800_ref18","volume-title":"Females Are Mosaics: X Inactivation and Sex Differences in Disease","author":"Migeon","year":"2014"},{"key":"2021100513225405800_ref19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40246-018-0185-z","article-title":"The X chromosome and sex-specific effects in infectious disease susceptibility","volume":"13","author":"Schurz","year":"2019","journal-title":"Hum. Genomics"},{"key":"2021100513225405800_ref20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neuron.2013.10.051","article-title":"Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease","volume":"81","author":"Wu","year":"2014","journal-title":"Neuron"},{"key":"2021100513225405800_ref21","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1038\/s41467-019-13340-w","article-title":"Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age","volume":"10","author":"Zito","year":"2019","journal-title":"Nat. Commun."},{"key":"2021100513225405800_ref22","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1399-0004.2004.00310.x","article-title":"The dynamics of X-inactivation skewing as women age","volume":"66","author":"Hatakeyama","year":"2004","journal-title":"Clin. Genet."},{"key":"2021100513225405800_ref23","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.semcdb.2016.03.009","article-title":"X inactivation and reactivation in X-linked diseases","volume":"56","author":"Vacca","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"2021100513225405800_ref24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1055\/s-2001-15395","article-title":"Ring X and other structural X chromosome abnormalities: X inactivation and phenotype","volume":"19","author":"Leppig","year":"2001","journal-title":"Semin. Reprod. Med."},{"key":"2021100513225405800_ref25","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/ng1197-353","article-title":"A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation","volume":"17","author":"Plenge","year":"1997","journal-title":"Nat. Genet."},{"key":"2021100513225405800_ref26","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/brain\/awt361","article-title":"X-linked adrenoleukodystrophy in women: a cross-sectional cohort study","volume":"137","author":"Engelen","year":"2014","journal-title":"Brain"},{"key":"2021100513225405800_ref27","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1086\/301651","article-title":"Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism","volume":"61","author":"Lau","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"2021100513225405800_ref28","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/0896-6273(89)90226-2","article-title":"Dystrophin abnormalities in Duchenne\/Becker muscular dystrophy","volume":"2","author":"Hoffman","year":"1989","journal-title":"Neuron"},{"key":"2021100513225405800_ref29","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1136\/jmg.23.6.484","article-title":"Muscular dystrophy in girls with X; autosome translocations","volume":"23","author":"Boyd","year":"1986","journal-title":"J. Med. Genet."},{"key":"2021100513225405800_ref30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1750-1172-5-14","article-title":"Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review","volume":"5","author":"Pinto","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"2021100513225405800_ref31","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1750-1172-8-92","article-title":"Clinical manifestations in female carriers of mucopolysaccharidosis type II: a Spanish cross-sectional study","volume":"8","author":"Guill\u00e9n-Navarro","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"2021100513225405800_ref32","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ymgme.2014.11.005","article-title":"Absence of \u03b1-galactosidase cross-correction in Fabry heterozygote cultured skin fibroblasts","volume":"114","author":"Fuller","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"2021100513225405800_ref33","doi-asserted-by":"crossref","first-page":"100529","DOI":"10.1016\/j.ymgmr.2019.100529","article-title":"Comment: why are females with Fabry disease affected?","volume":"21","author":"Beck","year":"2019","journal-title":"Mol Genet Metab Rep"},{"key":"2021100513225405800_ref34","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1073\/pnas.67.3.1573","article-title":"Evidence for transfer of enzyme product as the basis of metabolic cooperation between tissue culture fibroblasts of Lesch-Nyhan disease and normal cells","volume":"67","author":"Cox","year":"1970","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref35","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1093\/hmg\/ddt015","article-title":"Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes","volume":"22","author":"Twigg","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2021100513225405800_ref36","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1007\/s10803-015-2519-1","article-title":"Brief report: systematic review of Rett syndrome in males","volume":"45","author":"Reichow","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"2021100513225405800_ref37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41586-020-2703-0","article-title":"A protein assembly mediates Xist localization and gene silencing","volume":"587","author":"Pandya-Jones","year":"2020","journal-title":"Nature"},{"key":"2021100513225405800_ref38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1008333","article-title":"Xist RNA in action: past, present, and future","volume":"15","author":"Loda","year":"2019","journal-title":"PLoS Genet."},{"key":"2021100513225405800_ref39","doi-asserted-by":"crossref","first-page":"14412","DOI":"10.1073\/pnas.96.25.14412","article-title":"The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome","volume":"96","author":"Hansen","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref40","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41594-018-0111-z","article-title":"Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters","volume":"25","author":"Jansz","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021100513225405800_ref41","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nsmb.2532","article-title":"Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway","volume":"20","author":"Nozawa","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021100513225405800_ref42","doi-asserted-by":"crossref","first-page":"397","DOI":"10.18314\/cogo.v4i1.2073","article-title":"The human female paradox: biological disadvantage preimplantation, biological advantage, thereafter","volume":"4","author":"Migeon","year":"2021","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"2021100513225405800_ref43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.stem.2013.11.022","article-title":"The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network","volume":"14","author":"Schulz","year":"2014","journal-title":"Cell Stem Cell"},{"key":"2021100513225405800_ref44","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13059-021-02321-2","article-title":"Identification of X-chromosomal genes that drive sex differences in embryonic stem cells through a hierarchical CRISPR screening approach","volume":"22","author":"Genolet","year":"2021","journal-title":"Genome Biol."},{"key":"2021100513225405800_ref45","article-title":"Single-cell landscape of nuclear configuration and gene expression during stem cell differentiation and X inactivation","author":"Bonora","year":"2020","journal-title":"bioRxiv"},{"key":"2021100513225405800_ref46","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3389\/fcell.2019.00219","article-title":"X inactivation and escape: epigenetic and structural features","volume":"7","author":"Fang","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"2021100513225405800_ref47","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00439-011-1011-z","article-title":"Genes that escape from X inactivation","volume":"130","author":"Berletch","year":"2011","journal-title":"Hum. Genet."},{"key":"2021100513225405800_ref48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13293-015-0053-7","article-title":"Derivation of consensus inactivation status for X-linked genes from genome-wide studies","volume":"6","author":"Balaton","year":"2015","journal-title":"Biol. Sex Differ."},{"key":"2021100513225405800_ref49","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature03479","article-title":"X-inactivation profile reveals extensive variability in X-linked gene expression in females","volume":"434","author":"Carrel","year":"2005","journal-title":"Nature"},{"key":"2021100513225405800_ref50","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nature24265","article-title":"Landscape of X chromosome inactivation across human tissues","volume":"550","author":"Tukiainen","year":"2017","journal-title":"Nature"},{"key":"2021100513225405800_ref51","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.tig.2016.03.007","article-title":"Escape artists of the X chromosome","volume":"32","author":"Balaton","year":"2016","journal-title":"Trends Genet."},{"key":"2021100513225405800_ref52","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1101\/gr.103200.109","article-title":"Global survey of escape from X inactivation by RNA-sequencing in mouse","volume":"20","author":"Yang","year":"2010","journal-title":"Genome Res."},{"key":"2021100513225405800_ref53","doi-asserted-by":"crossref","first-page":"E2882","DOI":"10.1073\/pnas.1611905114","article-title":"Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain","volume":"114","author":"Keown","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref54","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nature13206","article-title":"Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators","volume":"508","author":"Bellott","year":"2014","journal-title":"Nature"},{"key":"2021100513225405800_ref55","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/nature13151","article-title":"Origins and functional evolution of Y chromosomes across mammals","volume":"508","author":"Cortez","year":"2014","journal-title":"Nature"},{"key":"2021100513225405800_ref56","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1086\/302556","article-title":"Polymorphic X-chromosome inactivation of the human TIMP1 gene","volume":"65","author":"Anderson","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"2021100513225405800_ref57","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005079","article-title":"Escape from X inactivation varies in mouse tissues","volume":"11","author":"Berletch","year":"2015","journal-title":"PLoS Genet."},{"key":"2021100513225405800_ref58","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12864-019-5507-6","article-title":"Human genes escaping X-inactivation revealed by single cell expression data","volume":"20","author":"Wainer Katsir","year":"2019","journal-title":"BMC Genomics"},{"key":"2021100513225405800_ref59","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaz5677","article-title":"A second X chromosome contributes to resilience in a mouse model of Alzheimer\u2019s disease","volume":"12","author":"Davis","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"2021100513225405800_ref60","doi-asserted-by":"crossref","first-page":"3852","DOI":"10.1172\/JCI126250","article-title":"The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity","volume":"129","author":"Itoh","year":"2019","journal-title":"J. Clin. Invest."},{"key":"2021100513225405800_ref61","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.1093\/hmg\/ddz254","article-title":"Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders","volume":"28","author":"Poeta","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2021100513225405800_ref62","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1136\/jmedgenet-2018-105625","article-title":"Kabuki syndrome: international consensus diagnostic criteria","volume":"56","author":"Adam","year":"2019","journal-title":"J. Med. Genet."},{"key":"2021100513225405800_ref63","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1002\/ajmg.a.36442","article-title":"A three generation X-linked family with kabuki syndrome phenotype and a frameshift mutation in KDM6A","volume":"164A","author":"Lederer","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"2021100513225405800_ref64","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1002\/ajmg.a.37634","article-title":"De novo exonic deletion of KDM6A in a Chinese girl with kabuki syndrome: a case report and brief literature review","volume":"170","author":"Yang","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"2021100513225405800_ref65","first-page":"2588\u20132601","article-title":"Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving","volume":"30","author":"Zhang","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"2021100513225405800_ref66","doi-asserted-by":"crossref","first-page":"R242","DOI":"10.1093\/hmg\/ddy148","article-title":"The eXceptional nature of the X chromosome","volume":"27","author":"Balaton","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2021100513225405800_ref67","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0004175","article-title":"Studying early lethality of 45,XO (Turner's syndrome) embryos using human embryonic stem cells","volume":"4","author":"Urbach","year":"2009","journal-title":"PLoS One"},{"key":"2021100513225405800_ref68","doi-asserted-by":"crossref","first-page":"223","DOI":"10.5582\/irdr.2017.01056","article-title":"A basic understanding of Turner syndrome: incidence, complications, diagnosis, and treatment","volume":"7","author":"Cui","year":"2018","journal-title":"Intractable Rare Dis. Res."},{"key":"2021100513225405800_ref69","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1210\/jc.2012-2382","article-title":"Clinical review: Klinefelter syndrome--a clinical update","volume":"98","author":"Groth","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021100513225405800_ref70","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3109\/08916934.2014.968918","article-title":"Associations between Klinefelter's syndrome and autoimmune diseases: English national record linkage studies","volume":"48","author":"Seminog","year":"2015","journal-title":"Autoimmunity"},{"key":"2021100513225405800_ref71","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/ddrr.83","article-title":"The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors","volume":"15","author":"Boada","year":"2009","journal-title":"Dev. Disabil. Res. Rev."},{"key":"2021100513225405800_ref72","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1469-8749.2009.03545.x","article-title":"Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review","volume":"52","author":"Leggett","year":"2010","journal-title":"Dev. Med. Child Neurol."},{"key":"2021100513225405800_ref73","first-page":"935202","article-title":"A new case of prenatally diagnosed pentasomy x: review of the literature","volume":"2015","author":"Pirollo","year":"2015","journal-title":"Case Rep. Obstet. Gynecol."},{"key":"2021100513225405800_ref74","doi-asserted-by":"crossref","first-page":"7398","DOI":"10.1073\/pnas.1802889115","article-title":"Sex-chromosome dosage effects on gene expression in humans","volume":"115","author":"Raznahan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref75","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1091\/mbc.E18-06-0359","article-title":"Effects of human sex chromosome dosage on spatial chromosome organization","volume":"29","author":"Jowhar","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"2021100513225405800_ref76","doi-asserted-by":"crossref","first-page":"34220","DOI":"10.1038\/srep34220","article-title":"Widespread DNA hypomethylation and differential gene expression in Turner syndrome","volume":"6","author":"Trolle","year":"2016","journal-title":"Sci. Rep."},{"key":"2021100513225405800_ref77","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1003489","article-title":"Female bias in Rhox6 and 9 regulation by the histone demethylase KDM6A","volume":"9","author":"Berletch","year":"2013","journal-title":"PLoS Genet."},{"key":"2021100513225405800_ref78","doi-asserted-by":"crossref","first-page":"13740","DOI":"10.1038\/s41598-018-31780-0","article-title":"DNA hypermethylation and differential gene expression associated with Klinefelter syndrome","volume":"8","author":"Skakkeb\u00e6k","year":"2018","journal-title":"Sci. Rep."},{"key":"2021100513225405800_ref79","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1073\/pnas.1910003117","article-title":"Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage","volume":"117","author":"Zhang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref80","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13148-015-0112-2","article-title":"DNA methylation signature in peripheral blood reveals distinct characteristics of human X chromosome numerical aberrations","volume":"7","author":"Sharma","year":"2015","journal-title":"Clin. Epigenetics"},{"key":"2021100513225405800_ref81","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ajmg.c.31802","article-title":"Epigenetics and genomics in Klinefelter syndrome","volume":"184","author":"Skakkebaek","year":"2020","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021100513225405800_ref82","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/ajmg.c.31683","article-title":"Epigenetics and genomics in Turner syndrome","volume":"181","author":"Viuff","year":"2019","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021100513225405800_ref83","doi-asserted-by":"crossref","DOI":"10.1126\/science.aba3066","article-title":"The impact of sex on gene expression across human tissues","volume":"369","author":"Oliva","year":"2020","journal-title":"Science"},{"key":"2021100513225405800_ref84","doi-asserted-by":"crossref","first-page":"E2029","DOI":"10.1073\/pnas.1520113113","article-title":"Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref85","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1007050","article-title":"Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells","volume":"13","author":"Syrett","year":"2017","journal-title":"PLoS Genet."},{"key":"2021100513225405800_ref86","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cels.2015.06.003","article-title":"Individuality and variation of personal regulomes in primary human T cells","volume":"1","author":"Qu","year":"2015","journal-title":"Cell Syst"},{"key":"2021100513225405800_ref87","doi-asserted-by":"crossref","first-page":"3536","DOI":"10.1172\/JCI130312","article-title":"X-tra X: an escape to autoimmunity","volume":"129","author":"Wu","year":"2019","journal-title":"J. Clin. Invest."},{"key":"2021100513225405800_ref88","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aap8855","article-title":"TLR7 escapes X chromosome inactivation in immune cells","volume":"3","author":"Souyris","year":"2018","journal-title":"Sci. Immunol."},{"key":"2021100513225405800_ref89","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00281-018-0712-y","article-title":"Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation","volume":"41","author":"Souyris","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"2021100513225405800_ref90","doi-asserted-by":"crossref","first-page":"108485","DOI":"10.1016\/j.celrep.2020.108485","article-title":"Heterogeneous escape from X chromosome inactivation results in sex differences in type I IFN responses at the single human pDC level","volume":"33","author":"Hagen","year":"2020","journal-title":"Cell Rep."},{"key":"2021100513225405800_ref91","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1016\/j.celrep.2018.08.001","article-title":"Transcriptional and translational differences of microglia from male and female brains","volume":"24","author":"Guneykaya","year":"2018","journal-title":"Cell Rep."},{"key":"2021100513225405800_ref92","doi-asserted-by":"crossref","first-page":"457","DOI":"10.3389\/fimmu.2015.00457","article-title":"Female bias in systemic lupus erythematosus is associated with the differential expression of X-linked toll-like receptor 8","volume":"6","author":"McDonald","year":"2015","journal-title":"Front. Immunol."},{"key":"2021100513225405800_ref93","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1016\/j.cell.2021.02.015","article-title":"B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells","volume":"184","author":"Yu","year":"2021","journal-title":"Cell"},{"key":"2021100513225405800_ref94","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1038\/s41467-019-10106-2","article-title":"Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus","volume":"10","author":"Odhams","year":"2019","journal-title":"Nat. Commun."},{"key":"2021100513225405800_ref95","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.3389\/fphar.2020.01049","article-title":"Jieduquyuziyin prescription suppresses inflammatory activity of MRL\/lpr mice and their bone marrow-derived macrophages","volume":"11","author":"Ji","year":"2020","journal-title":"Front. Pharmacol."},{"key":"2021100513225405800_ref96","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1002\/art.23701","article-title":"Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome","volume":"58","author":"Scofield","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2021100513225405800_ref97","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrc1413","article-title":"X-chromosome genetics and human cancer","volume":"4","author":"Spatz","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2021100513225405800_ref98","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/emmm.200900053","article-title":"ConteXt of change\u2013X inactivation and disease","volume":"2","author":"Agrelo","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"2021100513225405800_ref99","first-page":"3\u201316","article-title":"Chromosomes, sex chromatin, and cancer","volume":"2","author":"Barr","year":"1957","journal-title":"Proc. Can. Cancer Conf."},{"key":"2021100513225405800_ref100","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1101\/gr.185926.114","article-title":"The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer","volume":"25","author":"Chalign\u00e9","year":"2015","journal-title":"Genome Res."},{"key":"2021100513225405800_ref101","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.cell.2013.01.034","article-title":"Xist RNA is a potent suppressor of hematologic cancer in mice","volume":"152","author":"Yildirim","year":"2013","journal-title":"Cell"},{"key":"2021100513225405800_ref102","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.stem.2012.03.008","article-title":"Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes","volume":"11","author":"Anguera","year":"2012","journal-title":"Cell Stem Cell"},{"key":"2021100513225405800_ref103","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13046-016-0420-1","article-title":"Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression","volume":"35","author":"Chen","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2021100513225405800_ref104","doi-asserted-by":"crossref","first-page":"1010428317690999","DOI":"10.1177\/1010428317690999","article-title":"Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p\/PDK1\/AKT axis in hepatocellular carcinoma","volume":"39","author":"Mo","year":"2017","journal-title":"Tumour Biol."},{"key":"2021100513225405800_ref105","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.gene.2016.07.055","article-title":"Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p","volume":"592","author":"Song","year":"2016","journal-title":"Gene"},{"key":"2021100513225405800_ref106","doi-asserted-by":"crossref","first-page":"6520","DOI":"10.1158\/1078-0432.CCR-13-0877","article-title":"The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression","volume":"19","author":"Salvador","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"2021100513225405800_ref107","first-page":"769","article-title":"Relationship of XIST expression and responses of ovarian cancer to chemotherapy","volume":"1","author":"Huang","year":"2002","journal-title":"Mol. Cancer Ther."},{"key":"2021100513225405800_ref108","article-title":"Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma","volume":"10","author":"Kang","year":"2015","journal-title":"PLoS One"},{"key":"2021100513225405800_ref109","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nrg.2016.145","article-title":"Mosaicism in health and disease - clones picking up speed","volume":"18","author":"Forsberg","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"2021100513225405800_ref110","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nrc2172","article-title":"The disappearing Barr body in breast and ovarian cancers","volume":"7","author":"Pageau","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"2021100513225405800_ref111","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1080\/14737159.2020.1853528","article-title":"Investigation of LOY in prostate, pancreatic, and colorectal cancers in males: a case-control study","volume":"20","author":"Asim","year":"2020","journal-title":"Expert. Rev. Mol. Diagn."},{"key":"2021100513225405800_ref112","doi-asserted-by":"crossref","first-page":"11843","DOI":"10.1038\/ncomms11843","article-title":"Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome","volume":"7","author":"Machiela","year":"2016","journal-title":"Nat. Commun."},{"key":"2021100513225405800_ref113","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cca.2018.03.016","article-title":"Long non coding RNA XIST as a prognostic cancer marker - a meta-analysis","volume":"482","author":"Zhou","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"2021100513225405800_ref114","doi-asserted-by":"crossref","first-page":"6053","DOI":"10.1038\/s41467-020-19879-3","article-title":"Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome","volume":"11","author":"Fang","year":"2020","journal-title":"Nat. Commun."},{"key":"2021100513225405800_ref115","doi-asserted-by":"crossref","first-page":"342","DOI":"10.3389\/fphys.2016.00342","article-title":"Insights into the regulatory role of non-coding RNAs in cancer metabolism","volume":"7","author":"Beltr\u00e1n-Anaya","year":"2016","journal-title":"Front. Physiol."},{"key":"2021100513225405800_ref116","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.cell.2013.09.042","article-title":"Hypermutation of the inactive X chromosome is a frequent event in cancer","volume":"155","author":"J\u00e4ger","year":"2013","journal-title":"Cell"},{"key":"2021100513225405800_ref117","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41588-019-0564-y","article-title":"Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer","volume":"52","author":"Akdemir","year":"2020","journal-title":"Nat. Genet."},{"key":"2021100513225405800_ref118","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1158\/1055-9965.EPI-11-0246","article-title":"Sex disparities in cancer mortality and survival","volume":"20","author":"Cook","year":"2011","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"2021100513225405800_ref119","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1016\/j.cell.2007.04.034","article-title":"FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2\/ErbB2 oncogene","volume":"129","author":"Zuo","year":"2007","journal-title":"Cell"},{"key":"2021100513225405800_ref120","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/ng.3726","article-title":"Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias","volume":"49","author":"Dunford","year":"2017","journal-title":"Nat. Genet."},{"key":"2021100513225405800_ref121","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/jnci\/92.1.24","article-title":"Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer","volume":"92","author":"Shriver","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"2021100513225405800_ref122","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fcell.2019.00169","article-title":"Recent advances in understanding the reversal of gene silencing during X chromosome reactivation","volume":"7","author":"Talon","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"2021100513225405800_ref123","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1038\/s41556-020-00607-4","article-title":"Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation","volume":"22","author":"Chitiashvili","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"2021100513225405800_ref124","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1073\/pnas.1621356114","article-title":"Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP\/TGF-\u03b2 superfamily as a regulator of XIST expression","volume":"114","author":"Sripathy","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"Suppl 2","key":"2021100513225405800_ref125","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12859-015-0859-7","article-title":"Effects of Mecp2 loss of function in embryonic cortical neurons: a bioinformatics strategy to sort out non-neuronal cells variability from transcriptome profiling","volume":"17","author":"Vacca","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"2021100513225405800_ref126","doi-asserted-by":"crossref","first-page":"7991","DOI":"10.1073\/pnas.1803792115","article-title":"Pharmacological reactivation of inactive X-linked","volume":"115","author":"Przanowski","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021100513225405800_ref127","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1093\/nar\/gkz1214","article-title":"Artificial escape from XCI by DNA methylation editing of the CDKL5 gene","volume":"48","author":"Halmai","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2021100513225405800_ref128","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1146\/annurev-genom-091212-153530","article-title":"X chromosome inactivation and epigenetic responses to cellular reprogramming","volume":"14","author":"Lessing","year":"2013","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"2021100513225405800_ref129","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.cell.2013.02.043","article-title":"Epigenetics of reprogramming to induced pluripotency","volume":"152","author":"Papp","year":"2013","journal-title":"Cell"},{"key":"2021100513225405800_ref130","doi-asserted-by":"crossref","first-page":"E518","DOI":"10.1210\/jc.2014-2780","article-title":"Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome","volume":"100","author":"Zitzmann","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab221\/40341145\/ddab221.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/R2\/R285\/40507501\/ddab221.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/R2\/R285\/40507501\/ddab221.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T01:07:18Z","timestamp":1633568838000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/R2\/R285\/6350437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":130,"journal-issue":{"issue":"R2","published-online":{"date-parts":[[2021,8,13]]},"published-print":{"date-parts":[[2021,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab221","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,10,15]]},"published":{"date-parts":[[2021,8,13]]}}}