{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T02:48:42Z","timestamp":1761965322151,"version":"3.40.5"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Noonan syndrome (NS) is the most common disease among RASopathies, characterized by short stature, distinctive facial features, congenital cardiac defects, and variable developmental delay. NS rarely presents with overt neurologic manifestations, in particular hydrocephalus. Recent evidence suggests that pathogenic variants in the gene <jats:italic>RRAS2<\/jats:italic> are a rare cause of NS. Specifically, an <jats:italic>RRAS2<\/jats:italic> pathogenic variant, p.Q72L, may be particularly severe, manifesting with lethal neurologic findings. Here, we report a NS patient with documented p.Q72L variant in <jats:italic>RRAS2<\/jats:italic>. The patient was identified in utero to have hydrocephalus and a Dandy Walker malformation. Postnatal examination revealed multiple dysmorphic features, some reminiscent of NS including low\u2010set posteriorly rotated ears, redundant nuchal skin, widely spaced nipples, and cryptorchidism. Despite suspicion of NS, results of a 14\u2010gene Noonan syndrome panel (Invitae) were negative. Follow\u2010up rapid whole exome sequencing revealed a de novo p.Q72L variant in <jats:italic>RRAS2<\/jats:italic>, a poorly studied gene recently identified as a cause of NS. The patient herein reported brings to three the total number of cases reported with the <jats:italic>RRAS2<\/jats:italic> p.Q72L pathogenic variant. All three documented patients presented with a particularly fulminant course of NS, which included hydrocephalus. <jats:italic>RRAS2<\/jats:italic>, specifically p.Q72L, should be considered in severe NS cases with neurologic manifestations.<\/jats:p>","DOI":"10.1002\/ajmg.a.62523","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T04:23:03Z","timestamp":1634444583000},"page":"364-368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The <scp><i>RRAS2<\/i><\/scp> pathogenic variant p.<scp>Q72L<\/scp> produces severe Noonan syndrome with hydrocephalus: A case report"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9065-4176","authenticated-orcid":false,"given":"Nadav I.","family":"Weinstock","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Pediatrics Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo  New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurie","family":"Sadler","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo  New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"volume-title":"GeneReviews\u00ae [Internet]","author":"Allanson, J. 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