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Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    , which encodes the nonreceptor SH2 domain\u2010containing protein tyrosine phosphatase SHP2. Individual\n                    <jats:italic>PTPN11<\/jats:italic>\n                    mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    . While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that\n                    <jats:italic>PTPN11<\/jats:italic>\n                    mutations causing this condition act through an alternative dominant mechanism.\n                  <\/jats:p>","DOI":"10.1111\/cge.13904","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T04:49:55Z","timestamp":1608785395000},"page":"457-461","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Compound heterozygosity for\n                    <scp>PTPN11<\/scp>\n                    variants in a subject with Noonan syndrome provides insights into the mechanism of\n                    <scp>SHP2<\/scp>\n                    \u2010related disorders"],"prefix":"10.1111","volume":"99","author":[{"given":"Rebeca","family":"Lorca","sequence":"first","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares\u2010HUCA, Hospital Universitario Central de Asturias (HUCA) \u2013 Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA)  Oviedo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Pannone","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Ges\u00f9, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u00edas","family":"Cuesta\u2010Llavona","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares\u2010HUCA, Hospital Universitario Central de Asturias (HUCA) \u2013 Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA)  Oviedo Spain"},{"name":"Grupo Eje Cardio\u2010Renal Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias  Oviedo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianfranco","family":"Bocchinfuso","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Chimiche Universit\u00e0 di Roma Tor Vergata  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Rodr\u00edguez\u2010Reguero","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares\u2010HUCA, Hospital Universitario Central de Asturias (HUCA) \u2013 Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA)  Oviedo Spain"},{"name":"Grupo Eje Cardio\u2010Renal Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias  Oviedo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Carpentieri","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Ges\u00f9, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Hernando","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares\u2010HUCA, Hospital Universitario Central de Asturias (HUCA) \u2013 Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA)  Oviedo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Flex","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Ges\u00f9, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-9150","authenticated-orcid":false,"given":"Eliecer","family":"Coto","sequence":"additional","affiliation":[{"name":"Unidad de Referencia de Cardiopat\u00edas Familiares\u2010HUCA, Hospital Universitario Central de Asturias (HUCA) \u2013 Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA)  Oviedo Spain"},{"name":"Grupo Eje Cardio\u2010Renal Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias  Oviedo Spain"},{"name":"Medicine Department Universidad de Oviedo  Oviedo Spain"},{"name":"HUCA. 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