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However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single genetic mechanism can explain the phenotype and the variable expressivity, but several mechanisms may be at play concurrently. In this review, we describe different genetic mechanisms and recent advances in the understanding of the genome, epigenome, and transcriptome of KS and the link to the phenotype and clinical heterogeneity. Future studies are needed to unite clinical data, genomic data, and basic research attempting to understand the genetics behind KS. Unraveling the genetics of KS will be of clinical relevance as it may enable the use of polygenic risk scores to predict future disease susceptibility and enable clinical risk stratification of KS patients in the future.<\/jats:p>","DOI":"10.1002\/ajmg.c.31802","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T11:09:03Z","timestamp":1591096143000},"page":"216-225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Epigenetics and genomics in Klinefelter syndrome"],"prefix":"10.1002","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-4901","authenticated-orcid":false,"given":"Anne","family":"Skakkeb\u00e6k","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus N Denmark"},{"name":"Department of Endocrinology and Internal Medicine Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Viuff","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Internal Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten M.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-1720","authenticated-orcid":false,"given":"Claus H.","family":"Gravholt","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Internal Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2011.02246.x"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmi039"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02703336"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-015-0053-7"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-008-9272-8"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-36"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx014"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13206"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.1989.tb01297.x"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dew012"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2011.01223.x"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0777"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0697"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021491"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-0145"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0367"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.08.034"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.142"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13394"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7364"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03479"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.4238\/vol9-2gmr826"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/22.15.3181"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1530\/EC-19-0433"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2834"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7262.2007.00315.x"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007692"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45729"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1356-0"},{"key":"e_1_2_12_31_1","first-page":"3","article-title":"Androgen receptor structure, function and biology: From bench to bedside","volume":"37","author":"Davey R. 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