{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:56:24Z","timestamp":1782392184924,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Projects Coordination Unit of Istanbul University","award":["TYL-2023-40298"],"award-info":[{"award-number":["TYL-2023-40298"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Adenomyosis is a benign uterine disorder defined by the invagination of ectopic endometrial-like tissue into the myometrium, causing heavy menstrual bleeding and pain. While its pathogenesis remains unclear, shared-symptomology with endometriosis suggests a common mechanism. Adenomyosis is often diagnosed after age 40 due to its complex presentation and the need for histopathological confirmation, underscoring the need for non-invasive markers. Methods: Ten unrelated women with histopathological diagnosis of adenomyosis were recruited. All recruits completed the WERF-EPHect questionnaire and were additionally questioned about any comorbidities. Genomic DNA isolated from peripheral blood was subjected to whole exome sequencing (WES) on Illumina NovaSeq 6000 and was analyzed using the Pairend NGS Cloud platform. Variants were filtered for MAF &lt; 1% and were prioritized based on functional relevance and impact determined by in silico prediction tools. Variant selection adhered to stringent quality metrics to identify candidate variants associated with adenomyosis. Results: WES analysis did not reveal any variant common to the cohort. A total of eight pathogenic and two likely pathogenic novel variants were identified. Moreover, novel variants of p.(Val331Ile) in EFHB and p.(Phe14Val) in MEIS1 were the most frequently shared genetic variants in the cohort. Conclusions: Our findings suggest novel candidate genes for adenomyosis that warrant validation and functional investigation in larger, independent cohorts.<\/jats:p>","DOI":"10.3390\/diagnostics15233069","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:31:46Z","timestamp":1764689506000},"page":"3069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exome-Based Identification of Candidate Genes in Sporadic Adenomyosis Cases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-1839","authenticated-orcid":false,"given":"Feyza Nur","family":"Tuncer","sequence":"first","affiliation":[{"name":"Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimet","family":"Eser Ma","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences, Istanbul University, 34126 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7765-6124","authenticated-orcid":false,"given":"Sevcan","family":"Aydin","sequence":"additional","affiliation":[{"name":"Graduate School of Health Sciences, Istanbul University, 34126 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-9987","authenticated-orcid":false,"given":"Nura Fitnat","family":"Topbas Selcuki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Istanbul Sisli Hamidiye Etfal Training and Research Hospital, University of Health Sciences T\u00fcrkiye, 34453 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ipek","family":"Yildiz Ozaydin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences T\u00fcrkiye, 34303 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4123-6357","authenticated-orcid":false,"given":"Engin","family":"Oral","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Obstetrics and Gynaecology Unit, Norrland University Hospital, Ume\u00e5 University, 901 85 Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Moawad, G., Fruscalzo, A., Youssef, Y., Kheil, M., Tawil, T., Nehme, J., Pirtea, P., Guani, B., Afaneh, H., and Ayoubi, J.M. (2023). Adenomyosis: An Updated Review on Diagnosis and Classification. J. Clin. Med., 12.","DOI":"10.3390\/jcm12144828"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Xue, M., Leng, J., and Wong, F. (2021). Adenomyosis: Facts and Treatments, Springer Nature.","DOI":"10.1007\/978-981-33-4095-4"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1055\/s-0040-1716687","article-title":"Adenomyosis: Mechanisms and Pathogenesis","volume":"38","author":"Zhai","year":"2020","journal-title":"Semin. Reprod. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Breton, Z., Gouesbet, S., Indersie, E., Gabillet, M., Tran, V.-T., Aflak, N., Borghese, B., Petit, E., Roman, H., and Millepied, A.-C. (2025). Endometriosis Diagnostic Delay and Its Correlates: Results from the ComPaRe-Endometriosis Cohort. J. Women\u2019s Health.","DOI":"10.1177\/15409996251380129"},{"key":"ref_5","first-page":"33","article-title":"Adenomyosis: Diagnosis and Management","volume":"105","author":"Schrager","year":"2022","journal-title":"Am. Fam. Physician"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E363","DOI":"10.1503\/cmaj.220637","article-title":"Diagnosis and management of endometriosis","volume":"195","author":"Allaire","year":"2023","journal-title":"Can. Med Assoc. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41588-023-01323-z","article-title":"The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions","volume":"55","author":"Rahmioglu","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Harzif, A.K., Nurbaeti, P., Sayogo Putri, A., Silvana, V., Andyra, A.F., and Wiweko, B. (2024). Factors associated with delayed diagnosis of endometriosis: A systematic review. J. Endometr. Pelvic Pain Disord.","DOI":"10.1177\/22840265241291120"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.fertnstert.2014.07.1244","article-title":"World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research","volume":"102","author":"Vitonis","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"131","DOI":"10.52054\/FVVO.15.2.079","article-title":"Validation of the Turkish version of Endometriosis Health Profile questionnaire (EHP-30) to evaluate the quality of life in women with endometriosis","volume":"15","author":"Darici","year":"2023","journal-title":"Facts Views Vis. ObGyn"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.fertnstert.2014.07.1208","article-title":"World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research","volume":"102","author":"Rahmioglu","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ertorer, M.E., Tuncer, F.N., Ciftci, S., Tanrikulu, S., Selcukbiricik, O.S., Topalo\u011flu, \u00d6., Evran, M., Kadioglu, P., Aydin, S., and Can, B. (2025). Aryl hydrocarbon receptor interacting protein and syndromic gene variants detected in Turkish isolated pituitary adenoma families by whole exome sequencing. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-08610-1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2312","DOI":"10.1002\/mgg3.2312","article-title":"Whole exome sequencing reveals novel candidate variants for endometriosis utilizing multiple affected members in a single family","volume":"12","author":"Kina","year":"2024","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hammad, A.S., and Machaca, K. (2021). Store Operated Calcium Entry in Cell Migration and Cancer Metastasis. Cells, 10.","DOI":"10.3390\/cells10051246"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hodeify, R., Yu, F., Courjaret, R., Nader, N., Dib, M., Sun, L., Adap, E., Hubrack, S., and Machaca, K. (2017). Regulation and Role of Store-Operated Ca2+ Entry in Cellular Proliferation. Calcium Entry Channels in Non-Excitable Cells, CRC Press.","DOI":"10.1201\/9781315152592-12"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.fertnstert.2018.01.006","article-title":"Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis","volume":"109","author":"Gordts","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"230","DOI":"10.5152\/jtgga.2013.67763","article-title":"A close look at the contraction and relaxation of the myometrium; the role of calcium","volume":"14","author":"Bayrak","year":"2013","journal-title":"J. Turk. Ger. Gynecol. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1093\/humrep\/den082","article-title":"Myeloid ecotropic viral integration site 1 (MEIS) 1 involvement in embryonic implantation","volume":"23","author":"Xu","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.fertnstert.2010.09.060","article-title":"HOXA10 expression is decreased in endometrium of women with adenomyosis","volume":"95","author":"Fischer","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lazim, N., Elias, M.H., Sutaji, Z., Abdul Karim, A.K., Abu, M.A., Ugusman, A., Syafruddin, S.E., Mokhtar, M.H., and Ahmad, M.F. (2023). Expression of HOXA10 Gene in Women with Endometriosis: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612869"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1007\/s43032-025-01801-1","article-title":"MEIS1-mediated Apoptosis via TNFR1 in Endometriosis","volume":"32","author":"Wang","year":"2025","journal-title":"Reprod. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.mce.2012.12.019","article-title":"Disturbed balance between phase I and II metabolizing enzymes in ovarian endometriosis: A source of excessive hydroxy-estrogens and ROS?","volume":"367","author":"Hevir","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Alherz, F.A. (2024). Human sulfotransferase SULT2B1 physiological role and the impact of genetic polymorphism on enzyme activity and pathological conditions. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1464243"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1111\/jog.15969","article-title":"Knockdown of sulfotransferase 2B1 suppresses cell migration, invasion and promotes apoptosis in ovarian carcinoma cells via targeting annexin A9","volume":"50","author":"Gao","year":"2024","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.mce.2010.09.011","article-title":"Disturbed expression of phase I and phase II estrogen-metabolizing enzymes in endometrial cancer: Lower levels of CYP1B1 and increased expression of S-COMT","volume":"331","author":"Hevir","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Low, Y.L., Li, Y., Humphreys, K., Thalamuthu, A., Li, Y., Darabi, H., Wedr\u00e9n, S., Bonnard, C., Czene, K., and Iles, M.M. (2010). Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001012"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Dong, K., Jia, X., Du, S., Wang, D., Wang, L., Qu, H., Zhu, S., Wang, Y., and Wang, Z. (2023). A novel extrachromosomal circular DNA related genes signature for overall survival prediction in patients with ovarian cancer. BMC Med. Genom., 16.","DOI":"10.1186\/s12920-023-01576-x"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.7150\/jca.39626","article-title":"Association of benign gynaecological diseases and risk of endometrial and ovarian cancers","volume":"11","author":"Shen","year":"2020","journal-title":"J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Abouzid, M., Kruszyna, \u0141., Kaczmarek, D., Kagan, L., Mikulska-Sauermann, A.A., Filipowicz, D., Resztak, M., G\u0142\u00f3wka, F.K., and Kara\u017aniewicz-\u0141ada, M. (2025). Genetic Polymorphism of CYP2R1, CYP27A1, CYP27B1, and Vitamin D Metabolites Plasma Levels in Patients with Cardiovascular Disease: A Pilot Study. Biomolecules, 15.","DOI":"10.3390\/biom15050699"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"98","DOI":"10.4274\/tjod.galenos.2024.41662","article-title":"Vitamin D evaluation in adenomyosis: A retrospective cross-sectional study","volume":"21","author":"Yavuz","year":"2024","journal-title":"J. Turk. Soc. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, F., Yu, J., and Wang, C.-G. (2025). Association between ERCC2 Lys751Gln, Asp312Asn, and Arg156Arg polymorphisms and gynecological cancer susceptibility: A meta-analysis. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1461015"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1093\/biolre\/ioz150","article-title":"Genetic variants in the nucleotide excision repair genes are associated with the risk of developing endometriosis","volume":"101","author":"Shen","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Khan, K.N., Kitajima, M., Hiraki, K., Fujishita, A., Nakashima, M., and Masuzaki, H. (2015). Involvement of Hepatocyte Growth Factor-Induced Epithelial-Mesenchymal Transition in Human Adenomyosis1. Biol. Reprod., 92.","DOI":"10.1095\/biolreprod.114.124891"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.2147\/JIR.S497643","article-title":"Integration of Single Cell and Bulk RNA-Sequencing Reveals Key Genes and Immune Cell Infiltration to Construct a Predictive Model and Identify Drug Targets in Endometriosis","volume":"18","author":"Zhang","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.2174\/0109298673283426231220100011","article-title":"Development and Validation of the Diagnostic Model of 7 Gene in Endometriosis","volume":"31","author":"Zhu","year":"2024","journal-title":"Curr. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ejogrb.2013.06.036","article-title":"Molecular implication of ADAM-15 and 17 in intrauterine adhesions","volume":"170","author":"Liu","year":"2013","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:51:07Z","timestamp":1764690667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":36,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["diagnostics15233069"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15233069","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,2]]}}}