{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:57:51Z","timestamp":1785772671089,"version":"3.56.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    RASopathies are clinically and genetically heterogeneous disorders resulting from dysregulation of the RAS\/MAPK pathway. We present a single\u2010center retrospective cohort of 118 genotype\u2010confirmed pediatric patients diagnosed with RASopathy. Noonan syndrome was the most common clinical diagnosis, followed by NF\u2010Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. The most frequent clinical features included short stature, pulmonary stenosis, pectus deformities, and neurocognitive delay. Through molecular analysis, we identified distinct variants across major RAS\/MAPK pathway genes, with a considerable proportion of patients carrying rare or less frequently reported variants, including those in\n                    <jats:italic>LZTR1, RIT1, RAF1, HRAS, BRAF, RASA2, KRAS, CBL, SHOC2,<\/jats:italic>\n                    and\n                    <jats:italic>MAP2K2<\/jats:italic>\n                    . In addition to well\u2010established genotype\u2013phenotype correlations, we report several uncommon or previously unrecognized features: microcephaly in multiple\n                    <jats:italic>PTPN11<\/jats:italic>\n                    \u2010positive patients and renal agenesis in a child with a novel\n                    <jats:italic>HRAS<\/jats:italic>\n                    variant diagnosed with Costello syndrome. Furthermore, we identified three patients harboring\n                    <jats:italic>RASA2<\/jats:italic>\n                    variants, providing additional support for its emerging role in Noonan syndrome. This study expands the clinical and molecular spectrum of pediatric RASopathies. It emphasizes the need for comprehensive genetic evaluation and regular follow\u2010up in the context of overlapping clinical features, supporting accurate diagnosis and identifying candidates for emerging targeted therapies.\n                  <\/jats:p>","DOI":"10.1111\/cge.70193","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:56:26Z","timestamp":1780991786000},"page":"299-314","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Molecular Portraits of Pediatric\n                    <scp>RASopathies<\/scp>\n                    : A Study of 118 Genotype\u2010Confirmed Cases"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3847-1364","authenticated-orcid":false,"given":"Asl\u0131","family":"Gen\u00e7","sequence":"first","affiliation":[{"name":"Department of Pediatric Genetics University of Health Sciences, Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Sar\u0131kaya","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Health Sciences, Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet Cevdet","family":"Ceylan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Genetics Ankara Y\u0131ld\u0131r\u0131m Beyazit University  Ankara Turkey"},{"name":"Department of Medical Genetics Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0953-6210","authenticated-orcid":false,"given":"B\u00fc\u015franur","family":"\u00c7avdarl\u0131","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Genetics Ankara Y\u0131ld\u0131r\u0131m Beyazit University  Ankara Turkey"},{"name":"Department of Medical Genetics Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130brahim \u0130lker","family":"\u00c7etin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology University of Health Sciences, Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130lkay","family":"Erdo\u011fan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Ba\u015fkent University Ankara Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-1809","authenticated-orcid":false,"given":"Esra","family":"K\u0131l\u0131\u00e7","sequence":"additional","affiliation":[{"name":"Department of Pediatric Genetics University of Health Sciences, Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010genom\u2010091212\u2010153523"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2017\u201000232"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000276766"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20102\u20104"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw191"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61434"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010018\u20101951\u20107"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.21037\/tp\u201024\u2010113"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62529"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63905"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2024.10.002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/340847"},{"key":"e_1_2_9_14_1","first-page":"40","volume-title":"Noonan Syndrome and Related Disorders: A Matter of Deregulated Ras Signaling. Monographs in Human Genetics","author":"Sarkozy A.","year":"2008"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.1046415"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2015.03.021"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102020\u2010106892"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201090635\u20107"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21492"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35493"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21187"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2073"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010015\u20101627\u20105"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.021"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg\u20102024\u2010110253"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010025\u201003706\u20103"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431\u2010025\u201006611\u2010w"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2010.09.002"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114448"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.249"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13533"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63824"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61270"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.054411"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.75"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26083515"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20955"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1324128111"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70193","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70193","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70193","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:31:25Z","timestamp":1785771085000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/cge.70193"],"URL":"https:\/\/doi.org\/10.1111\/cge.70193","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]},"assertion":[{"value":"2025-12-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}