{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:10:24Z","timestamp":1764141024088,"version":"3.46.0"},"reference-count":26,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n Introduction<\/jats:title>\n \n IMAGe syndrome, a rare disorder caused by maternally inherited\n CDKN1C<\/jats:italic>\n pathogenic variants, is characterized by intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities. We report a novel intronic\n CDKN1C<\/jats:italic>\n variant in a 5\u2010year\u2010old Iranian girl with IMAGe syndrome.\n <\/jats:p>\n <\/jats:sec>\n \n Materials and Methods<\/jats:title>\n \n Clinical evaluations showed severe IUGR (birth weight 1850\u2009g), disproportionate short stature (height 88\u2009cm, \u22124.4\n Z<\/jats:italic>\n score), metaphyseal dysplasia, adrenal insufficiency (ACTH 1110\u2009pg\/mL, low cortisol), and dysmorphic features (frontal bossing, low\u2010set ears). Whole\u2010exome sequencing (WES) was performed to identify causative genetic variants.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n WES revealed a heterozygous\n CDKN1C<\/jats:italic>\n intronic variant, c.787+4A>T, absent from gnomAD, ExAC, and ClinVar. SpliceAI (score: 0.82) predicted disrupted splicing, potentially leading to a gain\u2010of\u2010function effect. The variant was consistently classified as a Variant of Uncertain Significance (VUS) according to ACMG\/AMP 2015 guidelines with 2020 updates. No other pathogenic variants were identified in genes related to skeletal dysplasia, adrenal insufficiency, or growth retardation. Sanger sequencing confirmed maternal inheritance in the proband, her healthy mother, and grandfather, consistent with\n CDKN1C<\/jats:italic>\n paternal imprinting.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n This case broadens the genetic spectrum of IMAGe syndrome by identifying the first reported intronic\n CDKN1C<\/jats:italic>\n variant associated with this condition. WES is crucial for diagnosis, and RNA analysis is needed to confirm the variant's functional impact. Rapid diagnosis is essential for managing life\u2010threatening adrenal insufficiency.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mgg3.70154","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T23:25:22Z","timestamp":1762903522000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Intronic Variant in\n \n CDKN1C<\/i>\n <\/scp>\n Gene Causing\n IMAGe<\/scp>\n Syndrome in an Iranian Girl"],"prefix":"10.1002","volume":"13","author":[{"given":"Setila","family":"Dalili","sequence":"first","affiliation":[{"name":"Pediatric Diseases Research Center Guilan University of Medical Sciences Rasht Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyyedeh Azade","family":"Hoseini Nouri","sequence":"additional","affiliation":[{"name":"Pediatric Diseases Research Center Guilan University of Medical Sciences Rasht Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ameneh","family":"Sharifi","sequence":"additional","affiliation":[{"name":"Growth and Development Research Tehran University of Medical Sciences Tehran Iran"},{"name":"Bahareh Medical Genetic Laboratory Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-5205","authenticated-orcid":false,"given":"Reza","family":"Bayat","sequence":"additional","affiliation":[{"name":"Pediatric Diseases Research Center Guilan University of Medical Sciences Rasht Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saeid","family":"Talebi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahram","family":"Savad","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Tehran University of Medical Sciences Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazanin","family":"Medghalchi","sequence":"additional","affiliation":[{"name":"Pediatric Diseases Research Center Guilan University of Medical Sciences Rasht Iran"},{"name":"Fraser International College (FIC) SFU Pathway Burnaby, British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1083-1660","authenticated-orcid":false,"given":"Bahareh","family":"Rabbani","sequence":"additional","affiliation":[{"name":"Growth and Development Research Tehran University of Medical Sciences Tehran Iran"},{"name":"Bahareh Medical Genetic Laboratory Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8614-1538","authenticated-orcid":false,"given":"Nejat","family":"Mahdieh","sequence":"additional","affiliation":[{"name":"Cardiogenetic Research Center Rajaie Cardiovascular Institute Tehran Iran"},{"name":"Fetal and Pediatric Cardiovascular Research Center, Children's Medical Center Tehran University of Medical Sciences Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2275"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33716"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab746"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107401"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-020-00945-y"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2021.05.006"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22824"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.galenos.2020.2020.0132"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2017.08.006"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2013.02.021"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2014.09.001"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075137"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12379"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0546-4"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3525"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.36.7.518"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1159\/000058105"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.10.024"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2003.09.052"},{"issue":"1","key":"e_1_2_13_21_1","first-page":"49","article-title":"The Frequency of Eight Common Point Mutations in CYP21 Gene in Iranian Patients with Congenital Adrenal Hyperplasia","volume":"12","author":"Ramazani A.","year":"2008","journal-title":"Iranian Biomedical Journal"},{"issue":"2","key":"e_1_2_13_22_1","first-page":"104","article-title":"Delta (GJB6\u2010D13S1830) Is Not a Common Cause of Nonsyndromic Hearing Loss in the Iranian Population","volume":"8","author":"Riazalhosseine Y.","year":"2005","journal-title":"Archives of Iranian Medicine"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33453"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1515\/crpm-2014-0005"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.15016.1"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.12.6186"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.6065\/apem.2142150.075"}],"container-title":["Molecular Genetics & Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70154","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:06:10Z","timestamp":1764140770000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":26,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/mgg3.70154"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70154","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2025,11]]},"assertion":[{"value":"2025-08-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70154"}}