{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:44:20Z","timestamp":1792640660371,"version":"4.5.0"},"reference-count":37,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"RachiExtra","award":["L.183\/1987"],"award-info":[{"award-number":["L.183\/1987"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Duplications of the 15q11.2\u2013q13 region are primarily associated with neurodevelopmental disorders, while their endocrine implications remain poorly defined. The imprinted gene MKRN3, located within this locus, inhibits pubertal onset, and loss-of-function variants cause central precocious puberty. However, the clinical impact of increased MKRN3 dosage remains unclear. This study investigates whether paternally derived 15q11.2\u2013q13 duplications lead to MKRN3 overexpression and are associated with delayed pubertal maturation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Four patients with confirmed paternal 15q11.2\u2013q13 duplications were retrospectively evaluated. Clinical, auxological, hormonal, and radiological data were collected. Genetic characterization was performed using MS-MLPA, array-CGH, and whole-exome sequencing when possible. MKRN3 expression was assessed by RT-qPCR in peripheral blood samples and compared with Tanner and sex-matched controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All patients showed duplications involving the 15q11.2\u2013q13 region with confirmed paternal origin. RT-qPCR showed increased MKRN3 expression in 3 of the 4 patients, supporting a potential gene dosage effect. Clinically, patients presented with pubertal abnormalities ranging from delayed puberty with slow progression to hypogonadotropic hypogonadism. Longitudinal data in one patient showed that MKRN3 expression levels during pubertal progression remained elevated compared to controls at both timepoints. In one case, a variant in PROKR2 may have contributed to phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Paternally derived 15q11.2\u2013q13 duplications are associated with MKRN3 overexpression and delayed pubertal maturation. These findings suggest for the first time in humans a link between increased MKRN3 dosage and pubertal delay, expanding the phenotypic spectrum of dup15q syndrome and highlighting the importance of endocrine monitoring in affected individuals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag385","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:20:41Z","timestamp":1789672841000},"source":"Crossref","is-referenced-by-count":1,"title":["Pubertal delay in patients with paternally derived 15q11.2\u2013q13 duplication syndrome and\n                    <i>MKRN3<\/i>\n                    overexpression"],"prefix":"10.1210","author":[{"given":"Delfina","family":"Petrone","sequence":"first","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-9818","authenticated-orcid":false,"given":"Stefania","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Giacobbe","sequence":"additional","affiliation":[{"name":"Medical Genetics and Cardiomyology Clinical Unit, University of Campania \u201cLuigi Vanvitelli\u201d, Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Onore","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Esposito","sequence":"additional","affiliation":[{"name":"Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80131 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silverio","family":"Perrotta","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Miraglia del Giudice","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]},{"name":"Telethon Institute of Genetics and Medicine (TIGEM) , Pozzuoli 80078 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Grandone","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d , Naples 80138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"issue":"16","key":"2026102111423376100_dgag385-B1","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1002\/ajmg.a.32364","article-title":"Mechanisms of imprinting of the Prader-Willi\/Angelman region","volume":"146a","author":"Horsthemke","year":"2008","journal-title":"Am J Med Genet A"},{"issue":"10","key":"2026102111423376100_dgag385-B2","doi-asserted-by":"crossref","DOI":"10.3390\/genes15101304","article-title":"Chromosome 15q11-q13 duplication syndrome: a review of the literature and 14 new cases","volume":"15","author":"Bisba","year":"2024","journal-title":"Genes (Basel)"},{"issue":"6","key":"2026102111423376100_dgag385-B3","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/hmg\/8.6.1025","article-title":"Large genomic duplicons map to sites of instability in the Prader-Willi\/Angelman syndrome chromosome region (15q11-q13)","volume":"8","author":"Christian","year":"1999","journal-title":"Hum Mol Genet"},{"issue":"1","key":"2026102111423376100_dgag385-B4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ejmg.2013.10.008","article-title":"Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases","volume":"57","author":"Al Ageeli","year":"2014","journal-title":"Eur J Med Genet"},{"issue":"6","key":"2026102111423376100_dgag385-B5","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2007-8-6-r114","article-title":"Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes","volume":"8","author":"Makoff","year":"2007","journal-title":"Genome Biol"},{"issue":"21","key":"2026102111423376100_dgag385-B6","doi-asserted-by":"crossref","DOI":"10.3390\/ijms242115818","article-title":"Structural variation evolution at the 15q11-q13 disease-associated locus","volume":"24","author":"Paparella","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"3","key":"2026102111423376100_dgag385-B7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.pcl.2015.03.004","article-title":"Prader-willi, angelman, and 15q11-q13 duplication syndromes","volume":"62","author":"Kalsner","year":"2015","journal-title":"Pediatr Clin North Am"},{"issue":"4","key":"2026102111423376100_dgag385-B8","doi-asserted-by":"crossref","DOI":"10.1002\/brb3.3437","article-title":"Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11\u2013q13 imprinting region","volume":"14","author":"Mim","year":"2024","journal-title":"Brain Behav"},{"issue":"3","key":"2026102111423376100_dgag385-B9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.24911\/ejmcr.9-2401","article-title":"Duplication of the 15q11-13 region in a Moroccan patient with autism, intellectual deficiency and absence of speech\u2014a case report","volume":"10","author":"Zineb","year":"2026","journal-title":"EJMCR"},{"issue":"4","key":"2026102111423376100_dgag385-B10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/aur.1284","article-title":"The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature","volume":"6","author":"Urraca","year":"2013","journal-title":"Autism Res"},{"issue":"5","key":"2026102111423376100_dgag385-B11","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005993","article-title":"Parental origin of interstitial duplications at 15q11.2-q13.3 in schizophrenia and neurodevelopmental disorders","volume":"12","author":"Isles","year":"2016","journal-title":"PLoS Genet"},{"key":"2026102111423376100_dgag385-B12","doi-asserted-by":"crossref","DOI":"10.1155\/2021\/6662054","article-title":"15q duplication syndrome: report on the first patient from ecuador with an unusual clinical presentation","volume":"2021","author":"Ortiz-Prado","year":"2021","journal-title":"Case Rep Med"},{"issue":"1","key":"2026102111423376100_dgag385-B13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41431-023-01336-6","article-title":"Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles","volume":"32","author":"Parijs","year":"2024","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"2026102111423376100_dgag385-B14","doi-asserted-by":"crossref","first-page":"4056","DOI":"10.1038\/s41467-021-24359-3","article-title":"Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications","volume":"12","author":"Tamada","year":"2021","journal-title":"Nat Commun"},{"issue":"4","key":"2026102111423376100_dgag385-B15","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.stemcr.2023.02.002","article-title":"The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons","volume":"18","author":"Elamin","year":"2023","journal-title":"Stem Cell Reports"},{"issue":"26","key":"2026102111423376100_dgag385-B16","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1056\/NEJMoa1302160","article-title":"Central precocious puberty caused by mutations in the imprinted gene MKRN3","volume":"368","author":"Abreu","year":"2013","journal-title":"N Engl J Med"},{"issue":"5","key":"2026102111423376100_dgag385-B17","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1210\/jc.2014-4462","article-title":"Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls","volume":"100","author":"Hagen","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026102111423376100_dgag385-B18","doi-asserted-by":"crossref","first-page":"E1097","DOI":"10.1210\/jc.2013-3126","article-title":"Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3","volume":"99","author":"Macedo","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026102111423376100_dgag385-B19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1080\/gye.15.3.165.169","article-title":"Pubertal disorders in inv dup(15) syndrome","volume":"15","author":"Grosso","year":"2001","journal-title":"Gynecol Endocrinol"},{"issue":"11","key":"2026102111423376100_dgag385-B20","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1007\/s40618-022-01860-0","article-title":"MKRN3 circulating levels in Prader-Willi syndrome: a pilot study","volume":"45","author":"Mariani","year":"2022","journal-title":"J Endocrinol Invest"},{"issue":"2","key":"2026102111423376100_dgag385-B21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/jbmr.5650070204","article-title":"New approaches for interpreting projected bone densitometry data","volume":"7","author":"Carter","year":"1992","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2026102111423376100_dgag385-B22","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1210\/jc.2009-2057","article-title":"Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children","volume":"95","author":"Zemel","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2026102111423376100_dgag385-B23","doi-asserted-by":"crossref","unstructured":"Petrone D, Palumbo S, Giacobbe C, et al \u00a02026. Data from: Supplementary data\u2014Pubertal delay in patients with paternally derived 15q11.2-q13 duplication syndrome and MKRN3 overexpression. Zenodo. Deposited 21 August 2026. doi:10.5281\/zenodo.22043069","DOI":"10.1210\/clinem\/dgag385"},{"issue":"9","key":"2026102111423376100_dgag385-B24","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1530\/EC-21-0182","article-title":"The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls","volume":"10","author":"Li","year":"2021","journal-title":"Endocr Connect"},{"key":"2026102111423376100_dgag385-B25","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2022.991322","article-title":"MKRN3 role in regulating pubertal onset: the state of art of functional studies","volume":"13","author":"Palumbo","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"11","key":"2026102111423376100_dgag385-B26","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqac132","article-title":"Hypothalamic overexpression of makorin ring finger protein 3 results in delayed puberty in female mice","volume":"163","author":"Roberts","year":"2022","journal-title":"Endocrinology"},{"issue":"8","key":"2026102111423376100_dgag385-B27","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1210\/clinem\/dgaa331","article-title":"Heterozygous deletions in MKRN3 cause central precocious puberty without prader-willi syndrome","volume":"105","author":"Meader","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2026102111423376100_dgag385-B28","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat Rev Endocrinol"},{"issue":"2","key":"2026102111423376100_dgag385-B29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/ejhg.2008.206","article-title":"Kallmann syndrome","volume":"17","author":"Dod\u00e9","year":"2009","journal-title":"Eur J Hum Genet"},{"issue":"10","key":"2026102111423376100_dgag385-B30","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1093\/hmg\/ddad014","article-title":"A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism","volume":"32","author":"Wang","year":"2023","journal-title":"Hum Mol Genet"},{"issue":"1","key":"2026102111423376100_dgag385-B31","doi-asserted-by":"crossref","DOI":"10.1136\/bcr-2023-258042","article-title":"Additional mutation in PROKR2 and phenotypic differences in a Kallmann syndrome\/normosmic congenital hypogonadotropic hypogonadism family carrying FGFR1 missense mutation","volume":"17","author":"Ichioka","year":"2024","journal-title":"BMJ Case Rep"},{"issue":"5","key":"2026102111423376100_dgag385-B32","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"4","key":"2026102111423376100_dgag385-B33","doi-asserted-by":"crossref","first-page":"338","DOI":"10.4274\/jcrpe.galenos.2023.2023-4-4","article-title":"PROKR2 mutations in patients with short stature who have isolated growth hormone deficiency and multiple pituitary hormone deficiency","volume":"15","author":"Kardelen","year":"2023","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"2026102111423376100_dgag385-B34","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2023.1132787","article-title":"Phenotypic and genotypic landscape of PROKR2 in neuroendocrine disorders","volume":"14","author":"Martinez-Mayer","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2026102111423376100_dgag385-B35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s12020-017-1281-x","article-title":"MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study","volume":"59","author":"Grandone","year":"2018","journal-title":"Endocrine"},{"issue":"6","key":"2026102111423376100_dgag385-B36","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1210\/jc.2016-1488","article-title":"Circulating MKRN3 levels decline during puberty in healthy boys","volume":"101","author":"Busch","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026102111423376100_dgag385-B37","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1530\/EJE-15-1193","article-title":"Circulating makorin ring finger protein 3 levels decline in boys before the clinical onset of puberty","volume":"174","author":"Varimo","year":"2016","journal-title":"Eur J Endocrinol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag385\/71220876\/dgag385.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag385\/71220876\/dgag385.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:42:43Z","timestamp":1792597363000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article\/doi\/10.1210\/clinem\/dgag385\/8816869"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":37,"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgag385","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]},"article-number":"dgag385"}}