{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:25:33Z","timestamp":1792693533075,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005297","name":"Medical University of Bia\u0142ystok","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005297","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Prader\u2013Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11\u2013q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. This review synthesizes current evidence to clarify the mechanistic pathways linking imprinting defects and epigenetic dysregulation to neuropsychiatric outcomes in PWS. Published studies\u2014including patient-derived induced pluripotent stem cell (iPSC) models, animal knockout systems (e.g., Magel2-null models), transcriptomic and DNA methylation datasets, and human neuroimaging research\u2014were identified through targeted searches of PubMed and Web of Science and integrated narratively rather than through systematic procedures. Across these data sources, deletion-type PWS is primarily associated with impaired neuronal maturation, altered serotonergic signaling, and locus-specific transcriptional dysregulation. Maternal uniparental disomy (mUPD) is characterized by broader epigenetic alterations within the imprinted domain, genome-wide transcriptional effects, dopaminergic pathway alterations, and disrupted prefrontal\u2013limbic connectivity linked to increased psychosis risk. Importantly, available evidence supports substantial phenotypic and mechanistic overlap between PWS subtypes, with genotype\u2013phenotype associations reflecting probabilistic tendencies rather than categorical distinctions. Collectively, convergent findings across molecular, neurochemical, and systems-level studies support a mechanistic continuum extending from imprinting defects to behavioral phenotypes. These insights position PWS as a translational model for understanding how epigenetic dysregulation contributes to psychiatric risk and highlight the need for genotype-informed, mechanistically grounded research to advance biomarker development and targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells15030268","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:49:44Z","timestamp":1770036584000},"page":"268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genomic Imprinting, Epigenetic Dysregulation, and Neuropsychiatric Mechanisms in Prader\u2013Willi Syndrome: A Multi-Level Integrative Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Zofia","family":"\u015aledzikowska","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Medical University of Bia\u0142ystok, Jana Kili\u0144skiego 1, 15-089 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5028-7829","authenticated-orcid":false,"given":"Xawery Eryk","family":"\u017bukow","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Bia\u0142ystok, Jana Kili\u0144skiego 1, 15-089 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzanna Ma\u0142gorzata","family":"Antos","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Bia\u0142ystok, Jana Kili\u0144skiego 1, 15-089 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7021-5133","authenticated-orcid":false,"given":"Napoleon","family":"Waszkiewicz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Medical University of Bialystok, Micha\u0142a Wo\u0142odyjowskiego 2, 15-272 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/gim.0b013e31822bead0","article-title":"Prader-Willi syndrome","volume":"14","author":"Cassidy","year":"2012","journal-title":"Genet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.6065\/apem.2016.21.3.126","article-title":"Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome","volume":"21","author":"Cheon","year":"2016","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/1573396315666190716120925","article-title":"Prader-Willi Syndrome\u2014Clinical Genetics, Diagnosis and Treatment Approaches: An Update","volume":"15","author":"Butler","year":"2019","journal-title":"Curr. Pediatr. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s40618-015-0312-9","article-title":"Prader-Willi syndrome: A review of clinical, genetic, and endocrine findings","volume":"38","author":"Angulo","year":"2015","journal-title":"J. Endocrinol. Investig."},{"key":"ref_5","first-page":"41","article-title":"Prader-Willi and Angelman Syndromes: Mechanisms and Management","volume":"16","author":"Ma","year":"2023","journal-title":"Appl. Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/ejhg.2014.103","article-title":"Highly restricted deletion of the SNORD116 region is implicated in Prader-Willi Syndrome","volume":"23","author":"Bieth","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e185159","DOI":"10.1172\/jci.insight.185159","article-title":"Investigation of a mouse model of Prader-Willi Syndrome with combined disruption of Necdin and Magel2","volume":"10","author":"Barelle","year":"2025","journal-title":"JCI Insight"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.omtm.2022.09.012","article-title":"Hypothalamic AAV-BDNF genetherapy improves metabolic function and behavior in the Magel2-null mouse model of Prader\u2013Willi syndrome","volume":"27","author":"Queen","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.ajhg.2024.05.023","article-title":"Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes","volume":"111","author":"Vorleuter","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","unstructured":"Driscoll, D.J., Miller, J.L., and Cassidy, S.B. (1993). Prader-Willi Syndrome. GeneReviews\u00ae, University of Washington."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.20945\/2359-3997000000248","article-title":"Prader\u2013Willi syndrome: Endocrine manifestations and management","volume":"64","author":"Alves","year":"2020","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3390\/endocrines3020027","article-title":"A Review of Prader\u2013Willi Syndrome","volume":"3","author":"Szabadi","year":"2022","journal-title":"Endocrines"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"579","DOI":"10.2147\/DMSO.S141352","article-title":"Obesity management in Prader-Willi syndrome: Current perspectives","volume":"11","author":"Fintini","year":"2018","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"274","DOI":"10.21037\/tp.2017.09.04","article-title":"Review of Prader-Willi syndrome: The endocrine approach","volume":"6","author":"Heksch","year":"2017","journal-title":"Transl. Pediatr."},{"key":"ref_15","unstructured":"Daley, S.F., Gutierrez, M.A.F., and Mendez, M.D. (2026, January 04). Prader\u2013Willi Syndrome, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK553161\/."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mahmoud, R., Kimonis, V., and Butler, M.G. (2023). Clinical trials in Prader\u2013Willi syndrome: A review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032150"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13757","DOI":"10.1093\/nar\/gkae1129","article-title":"Identifying key underlying regulatory networks and predicting targets of orphan C\/D box SNORD116 snoRNAs in Prader-Willi syndrome","volume":"52","author":"Gilmore","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"msab348","DOI":"10.1093\/molbev\/msab348","article-title":"Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader-Willi Syndrome","volume":"39","author":"Baldini","year":"2022","journal-title":"Mol. Biol. Evol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"240371","DOI":"10.1098\/rsob.240371","article-title":"Footprints in the Sno: Investigating the cellular and molecular mechanisms of SNORD116","volume":"15","author":"Holmes","year":"2025","journal-title":"Open Biol."},{"key":"ref_20","first-page":"4051","article-title":"Prader-Willi locus Snord116 RNA processing requires an active endogenous allele and neuron-specific splicing by Rbfox3\/NeuN","volume":"27","author":"Coulson","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","first-page":"AP1","article-title":"Prader-Willi syndrome proteins NDN and MAGEL2 are implicated in HPA axis regulation","volume":"83","author":"Dufour","year":"2022","journal-title":"Endocr. Abstr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6125","DOI":"10.1038\/s41467-025-61156-8","article-title":"Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome","volume":"16","author":"Wang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Good, D.J., and Kocher, M.A. (2017). Phylogenetic Analysis of the SNORD116 Locus. Genes, 8.","DOI":"10.3390\/genes8120358"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13148-021-01143-0","article-title":"Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory","volume":"13","author":"Salles","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100770","DOI":"10.1016\/j.xgen.2025.100770","article-title":"Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editing","volume":"5","author":"Rohm","year":"2025","journal-title":"Cell Genom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109974","DOI":"10.1016\/j.isci.2024.109974","article-title":"Deficiency in Prader\u2013Willi syndrome gene necdin leads to attenuated cardiac contractility","volume":"27","author":"Dong","year":"2024","journal-title":"iScience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/ajmg.b.30934","article-title":"Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behavior in mice null for the circadian rhythm output gene Magel2","volume":"150B","author":"Mercer","year":"2009","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Victor, A.K., Donaldson, M., Johnson, D., Miller, W., and Reiter, L.T. (2021). Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.747855"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Whittington, J., and Holland, A. (2022). Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012089"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00234-023-03259-x","article-title":"Aberrant brain intra- and internetwork functional connectivity in children with Prader\u2013Willi syndrome","volume":"66","author":"Huang","year":"2023","journal-title":"Neuroradiology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1365-2788.2006.00895.x","article-title":"The course and outcome of psychiatric illness in people with Prader-Willi syndrome: Implications for management and treatment","volume":"51","author":"Soni","year":"2007","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/dmcn.16018","article-title":"MAGEL2 (patho-)physiology and Schaaf-Yang syndrome","volume":"67","author":"Schubert","year":"2025","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1016\/j.ridd.2011.02.027","article-title":"Psychiatric illness in a cohort of adults with Prader\u2013Willi syndrome","volume":"32","author":"Sinnema","year":"2011","journal-title":"Res. Dev. Disabil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s11689-017-9188-7","article-title":"Altered functional resting-state hypothalamic connectivity and abnormal pituitary morphology in children with Prader\u2013Willi syndrome","volume":"9","author":"Lukoshe","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Costa, R.A., Ferreira, I.R., Cintra, H.A., Gomes, L.H.F., and Guida, L.C. (2019). Genotype\u2013phenotype relationships and endocrine findings in Prader\u2013Willi syndrome. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00864"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S2213-8587(21)00002-4","article-title":"Endocrine disorders in Prader\u2013Willi syndrome: A model to understand and treat hypothalamic dysfunction","volume":"9","author":"Tauber","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Madeo, S.F., Zagaroli, L., Vandelli, S., Calcaterra, V., Crin\u00f2, A., De Sanctis, L., Faienza, M.F., Fintini, D., Guazzarotti, L., and Licenziati, M.R. (2024). Endocrine features of Prader\u2013Willi syndrome: A narrative review focusing on genotype\u2013phenotype correlation. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1382583"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/nbm.2900","article-title":"Altered functional brain networks in Prader-Willi syndrome","volume":"26","author":"Zhang","year":"2013","journal-title":"NMR Biomed."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Huang, Z., and Cai, J. (2023). Progress in Brain Magnetic Resonance Imaging of Individuals with Prader-Willi Syndrome. J. Clin. Med., 12.","DOI":"10.3390\/jcm12031054"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1007\/s00787-024-02631-3","article-title":"Aberrant brain structural-functional coupling and structural\/functional network topology explain developmental delays in pediatric Prader-Willi syndrome","volume":"34","author":"Huang","year":"2025","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"fcac229","DOI":"10.1093\/braincomms\/fcac229","article-title":"In vivo neuroimaging evidence of hypothalamic alteration in Prader-Willi syndrome","volume":"4","author":"Brown","year":"2022","journal-title":"Brain Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1017\/S0140525X08004214","article-title":"Psychosis and autism as diametrical disorders of the social brain","volume":"31","author":"Crespi","year":"2008","journal-title":"Behav. Brain Sci."},{"key":"ref_43","first-page":"273","article-title":"The utilization of MS-MLPA as the first-line test for the diagnosis of Prader\u2013Willi syndrome in Thai patients","volume":"12","author":"Prapasrat","year":"2022","journal-title":"J. Pediatr. Genet."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T05:14:32Z","timestamp":1770095672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030268"],"URL":"https:\/\/doi.org\/10.3390\/cells15030268","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]}}}