{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:24:12Z","timestamp":1790627052616,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 21614"],"award-info":[{"award-number":["IG 21614"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss\u2010of\u2010function variants in\n                    <jats:italic>NF1<\/jats:italic>\n                    , encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    , encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain\u2010of\u2010function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    ). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported\n                    <jats:italic>PTPN11<\/jats:italic>\n                    variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant\n                    <jats:italic>PTPN11<\/jats:italic>\n                    variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic\n                    <jats:italic>NF1<\/jats:italic>\n                    variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.\n                  <\/jats:p>","DOI":"10.1111\/cge.14040","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T06:26:51Z","timestamp":1628058411000},"page":"563-572","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Clinical variability of neurofibromatosis 1: A modifying role of cooccurring\n                    <scp>\n                      <i>PTPN11<\/i>\n                    <\/scp>\n                    variants and atypical brain\n                    <scp>MRI<\/scp>\n                    findings"],"prefix":"10.1111","volume":"100","author":[{"given":"Alessandra","family":"D'Amico","sequence":"first","affiliation":[{"name":"Department of Advanced Biomedical Sciences University of Naples \u201cFederico II\u201d  Naples Italy"},{"name":"Tortorella Private Hospital  Salerno Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Rosano","sequence":"additional","affiliation":[{"name":"Translational Medical Sciences Department University of Naples \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Pannone","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division Pediatric Hospital Bambino Ges\u00f9, IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Pinna","sequence":"additional","affiliation":[{"name":"Medical Genetics Division Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Assunto","sequence":"additional","affiliation":[{"name":"Translational Medical Sciences Department University of Naples \u201cFederico II\u201d  Naples 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\u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Mariniello","sequence":"additional","affiliation":[{"name":"Translational Medical Sciences Department University of Naples \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Anna","family":"Siano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d  Salerno Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4547-0500","authenticated-orcid":false,"given":"Claudia","family":"Santoro","sequence":"additional","affiliation":[{"name":"Referral Centre of Neurofibromatosis, Department of Woman and Child, Specialistic and General Surgery University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-125X","authenticated-orcid":false,"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Strisciuglio","sequence":"additional","affiliation":[{"name":"Translational Medical Sciences Department University of Naples \u201cFederico II\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-8062","authenticated-orcid":false,"given":"Alessandro","family":"De 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