{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:54:18Z","timestamp":1790913258684,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"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":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Noonan syndrome (NS) and related RASopathies form a clinically and genetically heterogeneous group of disorders caused by germline dysregulation of the RAS\/MAPK pathway. Pathogenic variants in PTPN11 account for roughly half of classical NS, but the contribution of non\u2010PTPN11 genes in patients referred with NS or Noonan\u2010like phenotypes remains incompletely defined in several populations, including Russia. We characterized the spectrum of non\u2010PTPN11 variants in a large Russian cohort referred for suspected NS or Noonan\u2010like phenotypes and examined gene\u2010specific clinical patterns. We analyzed 456 unrelated patients with clinically diagnosed NS or Noonan\u2010related syndromes using a targeted panel of 23 RAS\/MAPK pathway genes. PTPN11 variants (23% of cases) were reported previously; here we focused on the remaining patients. Pathogenic or likely pathogenic variants were identified in 19% of cases (85\/456), with NF1, SOS1, SHOC2, and BRAF being the most frequently mutated genes, together accounting for 50% of the non\u2010PTPN11 diagnoses. Novel variants were observed in 12.1% of cases (7\/58 unique variants). Several genotype\u2013phenotype associations emerged: SOS1 mutations were associated with a high prevalence of cardiac defects, especially pulmonary stenosis and atrial septal defects (64% of patients,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01), whereas NF1 and SPRED1 cases had significantly fewer cardiac anomalies (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001 and\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05, respectively). Lentigines were predominantly seen in NF1 and SPRED1 patients (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), and all three evaluable males with MAP2K1 variants had cryptorchidism (3\/3). Conversely, BRAF\u2010mutated patients showed lower incidence of chest deformity (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) but higher rates of developmental delay. NF1, SOS1, SHOC2, and BRAF together accounted for half of the non\u2010PTPN11 molecular diagnoses in this Russian cohort, and the observed gene\u2010specific clinical patterns align with previous series, although limited subgroup sizes preclude firm individual associations.\n                  <\/jats:p>","DOI":"10.1111\/cge.70211","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:35:40Z","timestamp":1783053340000},"page":"527-537","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Spectrum of Non\u2010\n                    <scp>PTPN11<\/scp>\n                    Variants in Noonan Syndrome and Related\n                    <scp>RASopathies<\/scp>\n                    : Findings From a Russian Cohort"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-1844","authenticated-orcid":false,"given":"Anna","family":"Orlova","sequence":"first","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0351-1271","authenticated-orcid":false,"given":"Olga","family":"Shatokhina","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Guseva","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Demina","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Polyakov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-9093","authenticated-orcid":false,"given":"O\u0445ana","family":"Ryzkova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-091212-153523"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2010.09.002"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31156"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30295"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61270"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32012"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/340847"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes15030345"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1749"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01495.x"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124642"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.021"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.425"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1939"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31851"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1297\/cpe.2024-0005"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431\u2010022\u201004574\u2010w"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-15-14"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1159\/000276766"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/93.14.1062"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.915129"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70211","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70211","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:14:34Z","timestamp":1790910874000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":23,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1111\/cge.70211"],"URL":"https:\/\/doi.org\/10.1111\/cge.70211","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"assertion":[{"value":"2025-11-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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