{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:50:02Z","timestamp":1783432202977,"version":"3.54.6"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004332","name":"Seoul National University Hospital","doi-asserted-by":"publisher","award":["03-2022-0360"],"award-info":[{"award-number":["03-2022-0360"]}],"id":[{"id":"10.13039\/501100004332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith\u2013Wiedemann syndrome (BWS), two patients with Silver\u2013Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: <jats:italic>PPIEL<\/jats:italic> locus (chromosome 1: 39559298 to 39559744), and <jats:italic>FAM50B<\/jats:italic> locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci.<\/jats:p>","DOI":"10.1371\/journal.pone.0290450","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T17:28:33Z","timestamp":1692379713000},"page":"e0290450","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders"],"prefix":"10.1371","volume":"18","author":[{"given":"Hwa Young","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9813-1134","authenticated-orcid":true,"given":"Choong 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Monk","year":"2018","journal-title":"Epigenetics"},{"issue":"3","key":"pone.0290450.ref028","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.ajhg.2016.06.032","article-title":"DNA methylation profiling of uniparental disomy subjects provides a map of parental epigenetic bias in the human genome","volume":"99","author":"RS Joshi","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"18","key":"pone.0290450.ref029","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.2217\/epi-2022-0228","article-title":"Methylation status of VTRNA2-1\/nc886 is stable across populations, monozygotic twin pairs and in majority of tissues","volume":"14","author":"S Marttila","year":"2022","journal-title":"Epigenomics"},{"key":"pone.0290450.ref030","doi-asserted-by":"crossref","first-page":"988","DOI":"10.3389\/fneur.2019.00988","article-title":"Diagnostic yield of epilepsy panel testing in patients with seizure onset within the first year of life","volume":"10","author":"SS 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Kaneda","year":"2004","journal-title":"Nature"},{"issue":"4","key":"pone.0290450.ref039","first-page":"595","article-title":"Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes","volume":"34","author":"F Court","year":"2013","journal-title":"Hum Mutat"},{"issue":"4","key":"pone.0290450.ref040","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.mam.2012.06.009","article-title":"The role of imprinted genes in humans","volume":"34","author":"M Ishida","year":"2013","journal-title":"Mol Aspects Med"},{"key":"pone.0290450.ref041","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12881-016-0292-4","article-title":"Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57","volume":"17","author":"M Bak","year":"2016","journal-title":"BMC Med 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