Mutational analysis in a group of patients with Noonan syndrome, new mutations identified in SOS1

Introduction: Noonan Syndrome (NS) is an autosomal dominant congenital syndrome characterized by typical facial dysmorphology, heart defects and short stature. NS is genetically heterogeneous, germline mutations in four genes (PTPN11 , KRAS, SOS1 and RAF1) have been found, accounting for approximately 65% of cases. Methods and Results: We investigated 32 patients with NS diagnosed on the basis on Van der Burgt criteria, and we identified PTPN11 mutations in 50% of cases. The 16 patients negative for PTPN11 and KRAS mutations, underwent sequencing of the nine exons of SOS1, where mutations had been previously identified. In 4 cases (25%) one novel mutation (R497Q) and 3 previously described heterozygous mutations (M269T, Q477R and Y207H) were found. The M269T, Q477R mutations were found to be de novo, while the R497Q and Y207H mutations were found to be familial. The novel R497Q mutation was shown in the proband’s father and grandfather and it was not found in 300 control chromosomes from normal individuals. This proband’s showed the NS typical face and cardiac defects while the father and the grandfather showed only some abnormal ectodermal manifestations. The Y207H mutation was present in the proband’s mother, brother and grandfather, all of them carrying NS features. Clinically, all 4 patients with SOS1 mutations exhibited a clear NS phenotype, but, interestingly, these patients had normal stature with values ranging from the 9th to 49th centile, while short stature with or without GH deficiency was present in 70% of cases carrying the PTPN11 mutations. Conclusions: Four heterozygous SOS1 mutations have been found in 25% of NS patients negative for PTPN11 mutations. One SOS1 mutation (R497Q) has not yet been described. In contrast to the high frequency of short stature in patients carrying PTPN11 mutations, the SOS1 mutations do not seem to be associated with short stature.