{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:34:34Z","timestamp":1787236474602,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Executive Yuan, Taiwan","award":["MOST-110-2314-B-195-010-MY3"],"award-info":[{"award-number":["MOST-110-2314-B-195-010-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. The aim of this study was to identify the epigenotype-phenotype correlations of these patients using quantitative DNA methylation analysis. Methods: One hundred and four subjects with clinically suspected BWS were enrolled in this study. All of the subjects had been referred for diagnostic testing which was conducted using methylation profiling of H19-associated imprinting center (IC) 1 and KCNQ1OT1-associated IC2 in high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between the quantitative DNA methylation status and clinical manifestations of the enrolled subjects were analyzed. Results: Among the 104 subjects, 19 had IC2 hypomethylation, 2 had IC1 hypermethylation, and 10 had paternal uniparental disomy (pUPD). The subjects with IC2 hypomethylation were characterized by significantly more macroglossia but less hemihypertrophy compared to the subjects with pUPD (p &lt; 0.05). For 19 subjects with IC2 hypomethylation, the IC2 methylation level was significantly different (p &lt; 0.05) between the subjects with and without features including macroglossia (IC2 methylation level: 11.1% vs. 30.0%) and prenatal or postnatal overgrowth (8.5% vs. 16.9%). The IC2 methylation level was negatively correlated with birth weight z score (p &lt; 0.01, n = 19) and birth height z score (p &lt; 0.05, n = 13). For 36 subjects with clinically diagnosed BWS, the IC2 methylation level was negatively correlated with the BWS score (r = \u22120.592, p &lt; 0.01). The IC1 methylation level showed the tendency of positive correlation with the BWS score without statistical significance (r = 0.137, p &gt; 0.05). Conclusions: Lower IC2 methylation and higher IC1 methylation levels were associated with greater disease severity in the subjects with clinically diagnosed BWS. Quantitative DNA methylation analysis using the MassARRAY assay could improve the detection of epigenotype-phenotype correlations, which could further promote better genetic counseling and medical care for these patients.<\/jats:p>","DOI":"10.3390\/jpm11111066","type":"journal-article","created":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T22:06:16Z","timestamp":1635113176000},"page":"1066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Beckwith-Wiedemann Syndrome"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9619-0990","authenticated-orcid":false,"given":"Hsiang-Yu","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan"},{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"MacKay Junior College of Medicine, Nursing and Management, Taipei 10449, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 400, Taiwan"},{"name":"Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Lin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan"},{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"MacKay Junior College of Medicine, Nursing and Management, Taipei 10449, Taiwan"},{"name":"Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang-Ming University, Taipei 10449, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisca","family":"Fran","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Yi","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Hui","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dau-Ming","family":"Niu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Yang-Ming University, Taipei 10449, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei 10449, Taiwan"},{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ying","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, MacKay Memorial Hospital, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pao Chin","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 800, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Yin","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Pin","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5739-5216","authenticated-orcid":false,"given":"Chia-Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1057-3315","authenticated-orcid":false,"given":"Meng-Che","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Hung","family":"Chu","sequence":"additional","affiliation":[{"name":"Children Growth & Development Department, IHMED International Medical, Taipei 108, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9776-2092","authenticated-orcid":false,"given":"Chih-Kuang","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"College of Medicine, Fu-Jen Catholic University, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuan-Pei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan"},{"name":"Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Rare Disease Center, MacKay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/ejhg.2009.106","article-title":"Beckwith-Wiedemann syndrome","volume":"18","author":"Weksberg","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/ajmg.c.30267","article-title":"Beckwith-Wiedemann syndrome","volume":"154","author":"Choufani","year":"2010","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1399-0004.1994.tb04219.x","article-title":"Clinical features and natural history of Beckwith-Wiedemann syndrome: Presentation of 74 new cases","volume":"46","author":"Elliott","year":"1994","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/ajmg.c.31363","article-title":"Molecular findings in Beckwith-Wiedemann syndrome","volume":"163","author":"Choufani","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1868-7083-6-11","article-title":"Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1000 subjects","volume":"6","author":"Ibrahim","year":"2014","journal-title":"Clin. Epigenetics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S1028-4559(07)60002-3","article-title":"Syndromes and disorders associated with omphalocele (I): Beckwith-Wiedemann syndrome","volume":"46","author":"Chen","year":"2007","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1159\/000355544","article-title":"Beckwith-Wiedemann syndrome: Growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance","volume":"80","author":"Brioude","year":"2013","journal-title":"Horm. Res. Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/cge.12635","article-title":"(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: A paradigm for genomic medicine","volume":"89","author":"Mussa","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nrendo.2017.166","article-title":"Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: An international consensus statement","volume":"14","author":"Brioude","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ymgme.2016.07.003","article-title":"Epigenotype, genotype, and phenotype analysis of patients in Taiwan with Beckwith-Wiedemann syndrome","volume":"119","author":"Lin","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1002\/ajmg.a.36080","article-title":"Prevalence of Beckwith-Wiedemann syndrome in North West of Italy","volume":"161","author":"Mussa","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e20164311","DOI":"10.1542\/peds.2016-4311","article-title":"Assisted reproductive techniques and Risk of Beckwith-Wiedemann Syndrome","volume":"140","author":"Mussa","year":"2017","journal-title":"Pediatrics"},{"key":"ref_13","unstructured":"Beckwith, J.B. (1963, January 11). Extreme Cytomegaly of the Adrenal Fetal Cortex, Omphalocele, Hyperplasia of the Kidneys and Pancreas, and Leydig Cell Hyperplasia\u2013Another Syndrome?. Proceedings of the Annual Meeting of Western Society for Pediatric Research, Los Angeles, CA, USA."},{"key":"ref_14","first-page":"223","article-title":"Familial malformation complex with umbilical hernia and macroglossia\u2014A \u201cnew syndrome\u201d?","volume":"13","author":"Wiedemann","year":"1964","journal-title":"J. Genet. Hum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/ejhg.2013.132","article-title":"Clinical utility gene card for: Beckwith-Wiedemann Syndrome","volume":"22","author":"Eggermann","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1002\/ajmg.a.32966","article-title":"Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol","volume":"149","author":"Zarate","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/jhg.2013.67","article-title":"Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome","volume":"58","author":"Lee","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.4161\/epi.25812","article-title":"Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome","volume":"8","author":"Calvello","year":"2013","journal-title":"Epigenetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/sj.ejhg.5201912","article-title":"Japanese and North American\/European patients with Beckwith-Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations","volume":"15","author":"Sasaki","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1136\/jmg.37.12.921","article-title":"Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome","volume":"37","author":"Engel","year":"2000","journal-title":"J. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/sj.ejhg.5201463","article-title":"Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome","volume":"13","author":"Cooper","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/ejhg.2015.88","article-title":"(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome","volume":"24","author":"Mussa","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"653","DOI":"10.21037\/tp-20-243","article-title":"Phenotypes and epigenetic errors in patients with Beckwith-Wiedemann syndrome in China","volume":"9","author":"Zhang","year":"2020","journal-title":"Transl. Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13052-020-0819-3","article-title":"Clinical and molecular features of children with Beckwith-Wiedemann syndrome in China: A single-center retrospective cohort study","volume":"46","author":"Wang","year":"2020","journal-title":"Ital. J. Pediatrics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15785","DOI":"10.1073\/pnas.0507816102","article-title":"Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry","volume":"102","author":"Ehrich","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S1875-9572(10)60014-9","article-title":"New growth charts for Taiwanese children and adolescents based on World Health Organization standards and health-related physical fitness","volume":"51","author":"Chen","year":"2010","journal-title":"Pediatrics Neonatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3389\/fgene.2015.00287","article-title":"Design, measurement and processing of region-specific DNA methylation assays: The mass spectrometry-based method EpiTYPER","volume":"6","author":"Suchiman","year":"2015","journal-title":"Front. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/cge.12143","article-title":"Beckwith-Wiedemann and Silver-Russell syndromes: Opposite developmental imbalances in imprinted regulators of placental function and embryonic growth","volume":"84","author":"Jacob","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/ejhg.2008.197","article-title":"Determination of KCNQ1OT1 and H19 methylation levels in BWS and SRS patients using methylation-sensitive high-resolution melting analysis","volume":"17","author":"Alders","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/humu.20779","article-title":"Rapid detection of methylation change at H19 in human imprinting disorders using methylation-sensitive high-resolution melting","volume":"29","author":"Wojdacz","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1002\/ajmg.a.35831","article-title":"Bilateral pheochromocytomas, hemihyperplasia, and subtle somatic mosaicism: The importance of detecting low-level uniparental disomy","volume":"161","author":"Kalish","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1097\/01.ASN.0000023431.16173.55","article-title":"Renal abnormalities in beckwith-wiedemann syndrome are associated with 11p15.5 uniparental disomy","volume":"13","author":"Goldman","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00467-011-2009-4","article-title":"Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome","volume":"27","author":"Mussa","year":"2012","journal-title":"Pediatrics Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.tjog.2013.12.003","article-title":"Prenatal diagnosis of hypomethylation at KvDMR1 and Beckwith-Wiedemann syndrome in a pregnancy conceived by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer","volume":"53","author":"Chen","year":"2014","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1086\/341096","article-title":"Intracytoplasmic sperm injection may increase the risk of imprinting defects","volume":"71","author":"Cox","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1093\/humrep\/den406","article-title":"Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies","volume":"24","author":"Lim","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1086\/423902","article-title":"Beckwith-Wiedemann syndrome and IVF: A case-control study","volume":"75","author":"Halliday","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1086\/374824","article-title":"In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene","volume":"72","author":"Gicquel","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1136\/jmg.40.1.62","article-title":"Beckwith-Wiedemann syndrome and assisted reproduction technology (ART)","volume":"40","author":"Maher","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/ejhg.2015.224","article-title":"Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: A challenge for molecular analysis and genetic counseling","volume":"24","author":"Eggermann","year":"2016","journal-title":"Eur. J. Hum. Genet."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/11\/1066\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:47Z","timestamp":1760167307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/11\/1066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jpm11111066"],"URL":"https:\/\/doi.org\/10.3390\/jpm11111066","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,22]]}}}