{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T13:00:30Z","timestamp":1776517230205,"version":"3.51.2"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Women with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a \u201ctwo-hit\u201d hypothesis); 3) the previously reported association of autosomal <jats:italic>TIMP3<\/jats:italic> variants with CCA can be replicated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) <jats:italic>TIMP3<\/jats:italic> variance was investigated in relation to CCA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Standard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control\/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene\/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between <jats:italic>TIMP3<\/jats:italic> 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p&amp;lt;0.02).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes\/variants of interest emerged. A reported association between autosomal <jats:italic>TIMP3<\/jats:italic> variance and congenital cardiac anomalies was replicated.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1227164","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:32:50Z","timestamp":1695285170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Analysis of genetic variability in Turner syndrome linked to long-term clinical features"],"prefix":"10.3389","volume":"14","author":[{"given":"Jenifer P.","family":"Suntharalingham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miho","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoinette","family":"Cameron-Pimblett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinead M.","family":"McGlacken-Byrne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Buonocore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"del Valle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaganjit Kaur","family":"Madhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard S.","family":"Conway","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Achermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1159\/000487524","article-title":"Transition of care from childhood to adulthood: Turner syndrome","volume":"33","author":"Conway","year":"2018","journal-title":"Endocr Dev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnac016","article-title":"The changing face of Turner syndrome","volume":"44","author":"Gravholt","year":"2023","journal-title":"Endocr Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2013.77","article-title":"Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome","volume":"16","author":"Prakash","year":"2014","journal-title":"Genet Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13394","article-title":"The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan","volume":"87","author":"Cameron-Pimblett","year":"2017","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1159\/000178039","article-title":"Turner syndrome 2008","author":"Bondy","year":"2009","journal-title":"Horm Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.yapd.2022.03.004","article-title":"Turner syndrome","volume":"69","author":"Steiner","year":"2022","journal-title":"Adv Pediatr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvac108","article-title":"Management of a girl with delayed puberty and elevated gonadotropins","volume":"6","author":"McGlacken-Byrne","year":"2022","journal-title":"J Endocr Soc"},{"key":"B8","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/EJE-17-0430","article-title":"Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati international Turner syndrome meeting","volume":"177","author":"Gravholt","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1186\/s13023-022-02423-5","article-title":"Turner syndrome: French national diagnosis and care protocol (NDCP; national diagnosis and care protocol)","volume":"17","author":"Fiot","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-4356(97)00237-0","article-title":"Morbidity in turner syndrome","volume":"51","author":"Gravholt","year":"1998","journal-title":"J Clin Epidemiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/13697137.2018.1476969","article-title":"Care of the adult wOman with Turner syndrome","volume":"21","author":"Shah","year":"2018","journal-title":"Climacteric"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0558","article-title":"Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome","volume":"91","author":"Stochholm","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/1824-7288-39-79","article-title":"Endocrine autoimmunity in Turner syndrome","volume":"39","author":"Grossi","year":"2013","journal-title":"Ital J Pediatr"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-5955(00)00040-x","article-title":"Ear and hearing in relation to genotype and growth in Turner syndrome","volume":"144","author":"Barren\u00e4s","year":"2000","journal-title":"Hear Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37953","article-title":"Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry","volume":"170","author":"Prakash","year":"2016","journal-title":"Am J Med Genet A"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0384","article-title":"X-Chromosome gene dosage and the risk of diabetes in Turner Syndrome","volume":"94","author":"Bakalov","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01296.x","article-title":"Autoimmune thyroid syndrome in women with Turner\u2019s syndrome\u2013the association with karyotype","volume":"55","author":"Elsheikh","year":"2001","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0271-6","article-title":"Mosaic Turner syndrome shows reduced penetrance in an adult population study","volume":"21","author":"Tuke","year":"2019","journal-title":"Genet Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0224-4","article-title":"Turner syndrome: mechanisms and management","volume":"15","author":"Gravholt","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"B20","doi-asserted-by":"publisher","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 Epigenet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nature24265","article-title":"Landscape of X chromosome inactivation across human tissues","volume":"550","author":"Tukiainen","year":"2017","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","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"},{"key":"B23","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1002\/ajmg.c.31672","article-title":"How do genes that escape from X-chromosome inactivation contribute to Turner syndrome","volume":"181","author":"Peeters","year":"2019","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009532","article-title":"Evolutionary dynamics of the human pseudoautosomal regions","volume":"17","author":"Monteiro","year":"2021","journal-title":"PloS Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33334","article-title":"Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy","author":"Ottesen","year":"2010","journal-title":"Am J Med Genet A"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1159\/000049973","article-title":"Radiological signs of leri-weill dyschondrosteosis in turner syndrome","volume":"55","author":"Binder","year":"2001","journal-title":"Horm Res Paediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-112414-055311","article-title":"The biology and evolution of mamMalian Y chromosomes","volume":"49","author":"Hughes","year":"2015","journal-title":"Annu Rev Genet"},{"key":"B28","doi-asserted-by":"publisher","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":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn454","article-title":"Human DDX3 functions in translation and interacts with the translation initiation factor eIF3","volume":"36","author":"Lee","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","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"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31799","article-title":"Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome\u2014A comparison with Turner syndrome and 46,XX females","volume":"184","author":"Nielsen","year":"2020","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B32","doi-asserted-by":"publisher","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":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.928874","article-title":"Sex chromosome aneuploidies give rise to changes in the circular RNA profile: A circular transcriptome-wide study of Turner and Klinefelter syndrome across different tissues","volume":"13","author":"Johannsen","year":"2022","journal-title":"Front Genet"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00104","article-title":"Bioinformatic analysis identifies potential key genes in the pathogenesis of Turner Syndrome","volume":"11","author":"Wang","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007692","article-title":"TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome","volume":"14","author":"Corbitt","year":"2018","journal-title":"PloS Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31686","article-title":"The genetic basis of Turner syndrome aortopathy","volume":"181","author":"Corbitt","year":"2019","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.154671","article-title":"Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency","volume":"7","author":"McGlacken-Byrne","year":"2022","journal-title":"JCI Insight"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq003","article-title":"Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis","volume":"19","author":"Conlin","year":"2010","journal-title":"Hum Mol Genet"},{"key":"B39","unstructured":"R: A Language and Environment for Statistical Computing2022"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J Open Source Softw"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1039\/d1ay00821h","article-title":"An integrating strategy for serum metabolomics and microarray analysis to expand the understanding of diet-induced obesity","volume":"13","author":"Liu","year":"2021","journal-title":"Anal Methods"},{"key":"B43","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1136\/jmedgenet-2017-105113","article-title":"Mutations in IRS4 are associated with central hypothyroidism","volume":"55","author":"Heinen","year":"2018","journal-title":"J Med Genet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02538-0","article-title":"CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome","volume":"142","author":"Pinnaro","year":"2023","journal-title":"Hum Genet"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/JCI91913","article-title":"Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans","volume":"127","author":"Buonocore","year":"2017","journal-title":"J Clin Invest"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1765-3","article-title":"Genetic predisposition to mosaic Y chromosome loss in blood","volume":"575","author":"Thompson","year":"2019","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","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":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S13148-015-0112-2\/FIGURES\/7","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 Epigenet"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000213","article-title":"Host genetic and gut microbial signatures in familial inflammatory bowel disease","volume":"11","author":"Park","year":"2020","journal-title":"Clin Transl Gastroenterol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu072","article-title":"Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction","volume":"103","author":"Fan","year":"2014","journal-title":"Cardiovasc Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00661","article-title":"Biology of tissue inhibitor of metalloproteinase 3 (TIMP3), and its therapeutic implications in cardiovascular pathology","volume":"11","author":"Fan","year":"2020","journal-title":"Front Physiol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/cen.14907","article-title":"The TGF\u03b2 system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations","author":"Ridder","year":"2023","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.17605\/OSF.IO\/AJBEP","article-title":"Data from: Genetic variability in women with Turner syndrome","author":"Suntharalingham","year":"","journal-title":"Open Sci Framework"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1227164\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:32:55Z","timestamp":1695285175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1227164\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,20]]},"references-count":53,"alternative-id":["10.3389\/fendo.2023.1227164"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1227164","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,20]]},"article-number":"1227164"}}