IMPE Abstracts

RASopathies are a group of phenotypically overlapping syndromes caused by mutations that encode molecules of the Ras/MAPK signaling pathway. These disorders include: 1) Noonan syndrome caused by mutations in PTPN11, SOS1, RAF1, KRAS, BRAF and NRAS; 2) Noonan syndrome with multiple lentigines (NSML) caused by mutations in PTPN11, RAF1 and BRAF; 3) Costello syndrome caused by oncogenic mutations in HRAS; 4) cardio-facio-cutaneous (CFC) syndrome caused by mutations in BRAF, MAP2K1/2 and KRAS; 5) Noonan-like syndrome caused by mutations in SHOC2, PPP1CB or CBL; 6) neurofibromatosis type I caused by haploinsufficiency of NF1; 7) Legius syndrome caused by haploinsufficiency of SPRED1; 7) hereditary gingival fibromatosis caused by a loss-of-function mutation in SOS1; 8) capillary malformation-arteriovenous malformation caused by haploinsufficiency of RASA1 (p120 GAP). Recently, using next generation sequencing, novel variants in genes, including RIT1, MRAS, RRAS, RRAS2, RASA2, SOS2, LZTR1, MAPK1 and SPRED2, have been shown to be associated with Noonan syndrome. In addition, several mosaic RASopathies, including sebaceous nevi and Schimmelpenning syndrome, have been identified, further expanding thedisease spectrum. Our group has identified HRAS, BRAF, KRAS, RIT1 and RRAS2 mutations in patients with RASopathies (Aoki et al. Nat Genet, 2005; Niihori et al. Nat Genet 2006; Aoki et al. Am J Hum Genet 2013, Niihori et al. Am J Hum Genet 2019) and contributed to establish a disease entity of RASopathies. In this talk, molecular and phenotypic spectrum of Noonan syndrome and pathogenic mechanisms of RASopathies will be presented.