{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:46:06Z","timestamp":1789019166573,"version":"build-2803163510"},"reference-count":21,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Noonan syndrome (NS) due to the <jats:italic>RRAS2<\/jats:italic> gene, the pathogenic variant is an extremely rare RASopathies. Our objective was to identify the potential site of <jats:italic>RRAS2<\/jats:italic>, combined with the literature review, to find the correlation between clinical phenotype and genotype. De novo missense mutations affect different aspects of the <jats:italic>RRAS2<\/jats:italic> function, leading to hyperactivation of the RAS\u2010MAPK signaling cascade.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Conventional G\u2010banding was used to analyze the chromosome karyotype of the patient. Copy number variation sequencing (CNV\u2010seq) was used to detect the chromosomal gene microstructure of the patient and her parents. The exomes of the patient and her parents were sequenced using trio\u2010based whole exome sequencing (trio\u2010WES) technology. The candidate variant was verified by Sanger sequencing. The pathogenicity of the variant was predicted with a variety of bioinformatics tools.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Chromosome analysis of the proband revealed 46, XX, and no abnormality was found by CNV\u2010seq. After sequencing and bioinformatics filtering, the variant of <jats:italic>RRAS2<\/jats:italic>(c.67G&gt;T; p. Gly23Cys) was found in the proband, while the mutation was absent in her parents. To the best of our knowledge, our patient was with the typical Noonan syndrome, such as short stature, facial dysmorphism, and developmental delay. Furthermore, our study is the first case of NS with embryonal rhabdomyosarcoma (ERMS) caused by the <jats:italic>RRAS2<\/jats:italic> gene mutation reported in China.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our investigations suggested that the heterozygous missense of <jats:italic>RRAS2<\/jats:italic> may be a potential causal variant in a rare cause of Noonan syndrome, expanding our understanding of the causally relevant mutations for this disorder.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2313","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T09:49:00Z","timestamp":1699523340000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The <i>RRAS2<\/i> pathogenic variant (c.<scp>67G&gt;<\/scp>T; p. <scp>Gly23Cys<\/scp>) produces Noonan syndrome with embryonal rhabdomyosarcoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Lan","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Prenatal Diagnosis Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Prenatal Diagnosis Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu 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Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-8340","authenticated-orcid":false,"given":"Shuyao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Sichuan Provincial Maternity and Child Health Care Hospital  Chengdu 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