{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:24:11Z","timestamp":1790627051335,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,12,19]],"date-time":"2013-12-19T00:00:00Z","timestamp":1387411200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:sec><jats:label\/><jats:p>Neurofibromatosis\u2010Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS\u2010MAPK pathway. The major gene involved in NFNS is <jats:italic>NF1<\/jats:italic>, but co\u2010occurring <jats:italic>NF1<\/jats:italic> and <jats:italic>PTPN11<\/jats:italic> mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy\u2010associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including <jats:italic>NF1<\/jats:italic>, <jats:italic>PTPN11<\/jats:italic>, <jats:italic>SOS1<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, <jats:italic>RAF1<\/jats:italic>, <jats:italic>SHOC2<\/jats:italic>, <jats:italic>SPRED1<\/jats:italic>, <jats:italic>MAP2K1<\/jats:italic>, <jats:italic>MAP2K2<\/jats:italic>, and <jats:italic>CBL<\/jats:italic>. All three families harbored a heterozygous <jats:italic>NF1<\/jats:italic> variant, where the first family had a missense variant, c.5425C&gt;T;p.R1809C, the second family a recurrent 4bp\u2010deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice\u2010site variant, c.2991\u20101G&gt;A, resulting in skipping of exon 18 and an in\u2010frame deletion of 41 amino acids. These <jats:italic>NF1<\/jats:italic> variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991\u20101G&gt;A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in <jats:italic>NF1<\/jats:italic>, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for <jats:italic>NF1<\/jats:italic> mutations in NS patients, preferentially when caf\u00e9\u2010au\u2010lait spots are present. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36313","type":"journal-article","created":{"date-parts":[[2013,12,19]],"date-time":"2013-12-19T20:44:42Z","timestamp":1387485882000},"page":"579-587","source":"Crossref","is-referenced-by-count":36,"title":["Novel association of neurofibromatosis type 1\u2010causing mutations in families with neurofibromatosis\u2010noonan syndrome"],"prefix":"10.1002","volume":"164","author":[{"given":"Sara","family":"Ekvall","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Science for Life Laboratory, Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Sj\u00f6rs","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Central Hospital of V\u00e4ster\u00e5s V\u00e4ster\u00e5s Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Jonzon","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauno","family":"Vihinen","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science Lund University Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran","family":"Anner\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Science for Life Laboratory, Uppsala University Uppsala 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