%0 Journal Article %J Proc Natl Acad Sci U S A %D 2014 %T Next-generation sequencing identifies rare variants associated with Noonan syndrome. %A Chen, Peng-Chieh %A Yin, Jiani %A Yu, Hui-Wen %A Yuan, Tao %A Fernandez, Minerva %A Yung, Christina K %A Trinh, Quang M %A Peltekova, Vanya D %A Reid, Jeffrey G %A Tworog-Dube, Erica %A Morgan, Margaret B %A Muzny, Donna M %A Stein, Lincoln %A McPherson, John D %A Roberts, Amy E %A Gibbs, Richard A %A Neel, Benjamin G %A Kucherlapati, Raju %K Alleles %K Genetic Association Studies %K High-Throughput Nucleotide Sequencing %K Humans %K MAP Kinase Kinase 1 %K MAP Kinase Signaling System %K Mutation %K Neurofibromin 1 %K Noonan Syndrome %K ras Proteins %X

Noonan 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.

%B Proc Natl Acad Sci U S A %V 111 %P 11473-8 %8 2014 Aug 05 %G eng %N 31 %1 https://www.ncbi.nlm.nih.gov/pubmed/25049390?dopt=Abstract %R 10.1073/pnas.1324128111