Submission Details

There is a definitive association between alteration of the PTPN11 gene and the Noonan syndrome with multiple lentigines (NSML) 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 NSML (Digilio et al., 2002; Kim, Kim, Kim, Lee, & Lee, 2011; Lin, Wang, Chao, Wu, & Lin, 2009; Maridet et al., 2016; Motegi et al., 2015; Sarkozy, 2004). Additionally, the mechanism of disease has been characterized as LOF compared to that of PTPN11-NS, which is GOF (Edouard et al., 2010; Hanna et al., 2006; Marin et al., 2011; Stewart et al., 2010). The PTPN11 gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype and variants found in NSML patients in this gene disrupt the RAS pathway function as demonstrated by mouse and zebrafish models (Aoki et al., 2016; Marin et al., 2011; Rauen, 2013; Stewart et al., 2010). Variants observed in NSML patients are predicted to be neomorphic alleles with reduced phosphatase activity (e.g. p.Thr468Met) (Edouard et al., 2010; Hanna et al., 2006; Keilhack, David, McGregor, Cantley, & Neel, 2005; Kontaridis, Swanson, David, Barford, & Neel, 2006; Oishi et al., 2006; Oishi et al., 2009; Tartaglia et al., 2006; Yu et al., 2014). Of note, PTPN11 has also been classified as Definitive in association with NS 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 7/25/2018 (SOP Version 5).