RAS RAS KRAS NRAS HRAS 1 5 2 3 1 Fig. 1 GAPs 61  RAS 4 G12D 5 RAS 4 Noonan syndrome and related disorders 2 6 6 7 8 6 9 10 PTPN11 11 PTPN11 12 PTPN11 12 PTPN11 6 13 14 15 14 14 14 Fig. 2 a PTPN11 BRAF HRAS b PTPN11 MEK2 HRAS  PTPN11 16 NRAS KRAS NF1 17 19 20 21 22 19 PTPN11 PTPN11 23 24 PTPN11 23 25 PTPN11 26 27 6 25 PTPN11 PTPN11 28 30 31 Ptpn11 D61G/+ 32 PTPN11 Neurofibromatosis type 1 NF1 33 NF1 34 35 36 Nf1 Nf1 37 38 39 NF1 40 Additional genes mutated in Noonan syndrome PTPN11 41 42 46 RAS KRAS 42 KRAS PTPN11 KRAS KRAS 44 46 PTPN11 KRAS 42 42 KRAS 46 47 KRAS 48 PTPN11 KRAS 48 KRAS Genes mutated in cardio–facio–cutaneous syndrome 42 48 49 49 44 KRAS 42 46 48 48 BRAF 36 BRAF MEK1 MEK2 45 PTPN11 RAS BRAF 50 The molecular basis of Costello syndrome KRAS HRAS 43 51 53 54 55 56 HRAS BRAF 57 KRAS 48 HRAS Neuro–cardio–facial–cutaneous syndrome 42 44 46 RAS 58 3 Fig. 3 61  Neurofibromatosis Noonan syndrome and NS-like features in neurofibromatosis 59 NF1 PTPN11 60 NF1 40 59 NF1 NF1 NF1 4 Fig. 4 NF1 NF1  Work in progress KRAS BRAF MEK1 MEK2 HRAS PTPN11 KRAS BRAF MEK1 2 RAS Note added in proof SOS1 SOS1