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Am J Med Genet C Semin Med Genet. 2019 Mar;181(1):68-75. doi: 10.1002/ajmg.c.31683. Epub 2019 Feb 27.

Epigenetics and genomics in Turner syndrome.

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Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, Aarhus, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Biochemistry, Esbjerg Sygehus, Denmark.


The pathogenesis of Turner syndrome (TS) and the genotype-phenotype relationship has been thoroughly investigated during the last decade. It has become evident that the phenotype seen in TS does not only depend on simple gene dosage as a result of X chromosome monosomy. The origin of TS specific comorbidities such as infertility, cardiac malformations, bone dysgenesis, and autoimmune diseases may depend on a complex relationship between genes as well as transcriptional and epigenetic factors affecting gene expression across the genome. Furthermore, two individuals with TS with the exact same karyotype may exhibit completely different traits, suggesting that no conventional genotype-phenotype relationship exists. Here, we review the different genetic mechanisms behind differential gene expression, and highlight potential key-genes essential to the comorbidities seen in TS and other X chromosome aneuploidy syndromes. KDM6A, important for germ cell development, has shown to be differentially expressed and methylated in Turner and Klinefelter syndrome across studies. Furthermore, TIMP1/TIMP3 genes seem to affect the prevalence of bicuspid aortic valve. KDM5C could play a role in the neurocognitive development of Turner and Klinefelter syndrome. However, further research is needed to elucidate the genetic mechanism behind the phenotypic variability and the different phenotypic traits seen in TS.


Turner syndrome; X-inactivation; congenital malformations; infertility; sex chromosomes


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