{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:17:49Z","timestamp":1783012669540,"version":"3.54.6"},"reference-count":18,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["PNRR\u2010TR1\u20102023\u201012377161"],"award-info":[{"award-number":["PNRR\u2010TR1\u20102023\u201012377161"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["CUP I93C24000190006"],"award-info":[{"award-number":["CUP I93C24000190006"]}],"id":[{"id":"10.13039\/501100000780","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":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Noonan syndrome (NS) is a genetically heterogeneous disorder characterized by a broad spectrum of clinical features resulting from dysregulation of the RAS\/MAPK pathway. Although complex genotypes are increasingly recognized in NS, cases harboring two distinct pathogenic variants in different NS genes remain extremely rare. We describe the case of a 53\u2010year\u2010old female presenting a severe NS phenotype\u2014including short stature, facial dysmorphism, congenital heart defect, and developmental delay\u2014and concurrent acute myeloid leukemia (AML). Targeted NGS analysis of a RASopathy\u2010specific gene panel identified a constitutional heterozygous\n                    <jats:italic>PTPN11<\/jats:italic>\n                    variant (c.1472C&gt;T, p.(Pro491Leu)) and a mosaic\n                    <jats:italic>RIT1<\/jats:italic>\n                    variant (c.229G&gt;C, p.(Ala77Pro), 16.45% VAF), both meeting criteria for pathogenicity. The\n                    <jats:italic>RIT1<\/jats:italic>\n                    variant was validated via PCR\u2010RFLP across multiple tissues, excluding leukemia\u2010driven clonal expansion, and further quantified by\n                    <jats:italic>high\u2010depth<\/jats:italic>\n                    amplicon\u2010based sequencing. To our knowledge, this case represents a unique example of NS associated with pathogenic variants in two distinct RASopathy genes. Our findings underscore that comprehensive molecular characterization and multi\u2010tissue validation are essential for accurate diagnosis, genetic counseling, and personalized management, while also revealing that combinatorial RAS\/MAPK alterations may influence disease severity and clinical outcomes.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70135","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T05:24:39Z","timestamp":1774243479000},"page":"1879-1883","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complex Genetic Architecture in\n                    <scp>RASopathies<\/scp>\n                    : Constitutional\n                    <scp>\n                      <i>PTPN11<\/i>\n                    <\/scp>\n                    and Mosaic\n                    <scp>\n                      <i>RIT1<\/i>\n                    <\/scp>\n                    Pathogenic Variants Underlying Severe Noonan Syndrome With Adult\u2010Onset Acute Myeloid Leukemia"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8950-8595","authenticated-orcid":false,"given":"Francesco","family":"Prevedello","sequence":"first","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario Seif","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Medical Genetics and Rare Disease Coordination Unit AOU delle Marche  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Clinical Genetics Unit University Hospital of Verona  Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rigon","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Clinical Genetics Unit University Hospital of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Forzan","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit University Hospital of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Tacchetto","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Pediatric Research Institute (IRP)\u2014Fondazione Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Palmitessa","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Clinical Genetics Unit University Hospital of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Calosci","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Salviati","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Clinical Genetics Unit University Hospital of Padova  Padova Italy"},{"name":"Pediatric Research Institute (IRP)\u2014Fondazione Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Gurrieri","sequence":"additional","affiliation":[{"name":"Hematology Unit University Hospital of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Trevisson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Padova  Padova Italy"},{"name":"Clinical Genetics Unit University Hospital of Padova  Padova Italy"},{"name":"Pediatric Research Institute (IRP)\u2014Fondazione Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1159\/000505715"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-019-1463-1"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0004-27302010000800009"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32021"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14040"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33713"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33987"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-0658-0"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.249"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.37"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13904"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.09.007"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.24.00006"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32018"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26083515"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32012"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24044035"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0631"}],"container-title":["American 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