Chen, Peng-ChiehYin, JianiYu, Hui-WenYuan, TaoFernandez, MinervaYung, Christina K.Trinh, Quang M.Peltekova, Vanya D.Reid, Jeffrey G.Tworog-Dube, EricaMorgan, Margaret B.Muzny, Donna M.Stein, LincolnMcPherson, John D.Roberts, Amy E.Gibbs, Richard A.Neel, Benjamin G.Kucherlapati, Raju2019-10-142014Chen, P.-C., J. Yin, H.-W. Yu, T. Yuan, M. Fernandez, C. K. Yung, Q. M. Trinh, et al. 2014. “Next-Generation Sequencing Identifies Rare Variants Associated with Noonan Syndrome.” Proceedings of the National Academy of Sciences 111 (31): 11473–78. doi:10.1073/pnas.1324128111.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542975Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.en-USJournal Article2019-10-1410.1073/pnas.1324128111