{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T10:01:25Z","timestamp":1780308085957,"version":"3.54.0"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","award":["20240797"],"award-info":[{"award-number":["20240797"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    RASopathies are a group of genetic disorders caused by pathogenic variants in the RAS\u2010mitogen\u2010activated protein kinase (RAS\u2013MAPK) signaling pathway, often presenting with congenital heart defects, craniofacial dysmorphisms, and developmental delays. To assess the diagnostic yield of genetic testing in patients with suspected RASopathies and to identify predictive clinical \u201cred flags\u201d using machine learning (ML). This retrospective study included patients evaluated at our institution between 2020 and 2023. All patients underwent cardiovascular evaluation, and a subset of individuals with suspected RASopathies underwent genetic assessment including exome sequencing. Thirteen clinical \u201cred flags\u201d were analyzed as predictors of a molecular diagnosis within the subgroup of patients with suspected RASopathies. Diagnostic performance was assessed via sensitivity, specificity, and area under the curve (AUC). A random forest classifier identified the most predictive clinical features. Among 669 patients, 34 were clinically suspected of RASopathy, with a confirmed diagnosis in 24 cases (71%). Noonan syndrome was most frequent (18\/24), and PTPN11 was the most commonly mutated gene (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200913). Pulmonary valve stenosis (PVS) and facial dysmorphisms were the strongest individual predictors of a positive genetic test result. A threshold of \u2265\u20092 red flags balanced sensitivity (92%) and accuracy (73.5%). ML analysis identified PVS and facial dysmorphisms as the top predictors. A model including only these features achieved an AUC of 0.86 in the derivation cohort. PVS and facial dysmorphisms are key diagnostic indicators for RASopathies and should prompt early genetic testing. While the ML model showed high performance in this derivation cohort, external validation is needed to confirm its generalizability.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70119","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:34:11Z","timestamp":1773286451000},"page":"1608-1618","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing Diagnostic Accuracy of Clinical Red Flags in\n                    <scp>RASopathies<\/scp>"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8287-2448","authenticated-orcid":false,"given":"Emanuele","family":"Bobbio","sequence":"first","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Caiazza","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9304-988X","authenticated-orcid":false,"given":"Emanuele","family":"Monda","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giustina","family":"Aruta","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Budillon","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-200X","authenticated-orcid":false,"given":"Augusto","family":"Esposito","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide","family":"Fusco","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapaola","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Rubino","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Viscovo","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchino","family":"Scarano","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"},{"name":"Unit\u00e0 Operativa Semplice Dipartimentale (UOSD) Genetica Medica, Azienda Ospedaliera di Rilievo Nazionale (AORN)  Benevento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo Della","family":"Monica","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples 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 Italy"},{"name":"Telethon Institute of Genetics and Medicine (TIGEM)  Pozzuoli 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 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"Pecchia","sequence":"additional","affiliation":[{"name":"Research Unit of Intelligent Health Technology for Health and Wellbeing, Department of Engineering Universit\u00e0 Campus Bio\u2010Medico di Roma  Rome Italy"},{"name":"School of Engineering, University of Warwick  Coventry UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giovanna","family":"Russo","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8291-9517","authenticated-orcid":false,"given":"Giuseppe","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital  Naples Italy"},{"name":"Institute of Cardiovascular Science University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37736"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1542\/gr.46\u20105\u201059"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2024.02.025"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.03.050"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/gtmb.2009.0192"},{"issue":"3","key":"e_1_2_11_7_1","first-page":"134","article-title":"Genetic Evaluation and Management of Fetal Chylothorax: Review and Insights From a Case of Noonan Syndrome","volume":"42","author":"Chen C. H.","year":"2009","journal-title":"Lymphology"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/341528"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2008.06.011"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010018\u20100279\u20100"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.119.044794"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1176828"},{"issue":"4","key":"e_1_2_11_13_1","first-page":"184","article-title":"Management of Cardiovascular Disorders in Patients With Noonan Syndrome: A Case Report","volume":"12","author":"Khorgami M. R.","year":"2017","journal-title":"Journal of Tehran Heart Center"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13312-021-2092-y"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2022.03.050"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2021.07.004"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000937"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320210312"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200935"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36737"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038\u2010005\u20100239\u20107"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes15010032"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijscr.2020.05.048"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bj.2021.06.004"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(12)61023\u2010x"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124642"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20955"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20103\u201013"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2017\u201000232"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431\u2010005\u20101679\u2010y"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32012"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng772"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320530213"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003635"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10110847"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild\u20102021\u2010322858"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70119","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70119","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T09:07:47Z","timestamp":1780304867000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":36,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/ajmg.a.70119"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70119","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,11]]},"assertion":[{"value":"2025-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}