There is a definitive association between alteration of the PTPN11 gene and the Noonan syndrome (NS) phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in PTPN11 in patients with NS (Atik et al., 2016; Christensen, Yaish, Leon, Sola-Visner, & Agrawal, 2013; Demir, Yntema, Altincik, & Bober, 2010; Gulec, Ocak, Candan, Ataman, & Yarar, 2015; Jefferies, Belmont, Pignatelli, Towbin, & Craigen, 2010; Schollen, Matthijs, Gewillig, Fryns, & Legius, 2003; Tartaglia et al., 2001). Additionally, the mechanism of disease has been characterized as GOF due to increased activity, while PTPN11 variants associated with NS with multiple lentigines (NSML) are predicted to be neomorphic alleles with reduced phosphatase activity (Araki et al., 2004; Maridet, Sole, Morice-Picard, & Taieb, 2016; Oishi et al., 2006; Oishi et al., 2009; Pannone et al., 2017; Yu et al., 2014). The PTPN11 gene is also located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants found in NS patients in this gene disrupt the RAS pathway function as demonstrated by mouse and fly models (Araki et al., 2004; Oishi et al., 2006). Of note, PTPN11 has also been classified as Definitive in association with NSML and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating PTPN11 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/2018 (SOP Version 5).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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