{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T18:06:37Z","timestamp":1763748397905,"version":"build-2065373602"},"reference-count":20,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T00:00:00Z","timestamp":1620518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["24405"],"award-info":[{"award-number":["24405"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP15131"],"award-info":[{"award-number":["GGP15131"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Progetti per la ricerca oncologica della Regione Campania","award":["I-Cure"],"award-info":[{"award-number":["I-Cure"]}]},{"name":"Progetti competitivi intraAteneo\u201d Programma V:ALERE","award":["MIRIAM"],"award-info":[{"award-number":["MIRIAM"]}]},{"name":"European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA","award":["EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016\/739516"],"award-info":[{"award-number":["EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016\/739516"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and\/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.<\/jats:p>","DOI":"10.3390\/genes12050706","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T21:32:46Z","timestamp":1620595966000},"page":"706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-945X","authenticated-orcid":false,"given":"Angela","family":"Sparago","sequence":"first","affiliation":[{"name":"Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-3021","authenticated-orcid":false,"given":"Flavia","family":"Cerrato","sequence":"additional","affiliation":[{"name":"Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8835-5567","authenticated-orcid":false,"given":"Laura","family":"Pignata","sequence":"additional","affiliation":[{"name":"Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Cammarata-Scalisi","sequence":"additional","affiliation":[{"name":"Pediatrics Service, Regional Hospital of Antofagasta, 5935 Antofagasta, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Garavelli","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Mother and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmelo","family":"Piscopo","sequence":"additional","affiliation":[{"name":"Medical and Laboratory Genetics Unit, \u201cAntonio Cardarelli\u201d Hospital, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Vancini","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Maggiore Hospital, 40133 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Riccio","sequence":"additional","affiliation":[{"name":"Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"},{"name":"Institute of Genetics and Biophysics (IGB) \u201cAdriano Buzzati-Traverso\u201d, Consiglio Nazionale delle Ricerche (CNR), 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1101\/gad.11.8.973","article-title":"Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development","volume":"11","author":"Yan","year":"1997","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/387151a0","article-title":"Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome","volume":"387","author":"Zhang","year":"1997","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Andrews, S.C., Wood, M.D., Tunster, S.J., Barton, S.C., Surani, M.A., and John, R.M. 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