| Author |
Tworog-dube, Erica Trinh, Quang M. Yuan, Tao Mcpherson, John D. Gibbs, Richard A. Kucherlapati, Raju Yin, Jiani Muzny, Donna M. Stein, Lincoln Fernandez, Minerva Chen, Peng-chieh Roberts, Amy E. Peltekova, Vanya D. Yung, Christina K. Neel, Benjamin G. Reid, Jeffrey G. Morgan, Margaret B. Yu, Hui-wen |
| Description |
Author Affiliation: Chen PC ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Yin J ( Princess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7); Yu HW ( Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70457, Taiwan); Yuan T ( Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115); Fernandez M ( Princess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7); Yung CK ( Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Trinh QM ( Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Peltekova VD ( Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Reid JG ( Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030); Tworog-Dube E ( Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115); Morgan MB ( Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030); Muzny DM ( Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030); Stein L ( Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); McPherson JD ( Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3); Roberts AE ( Department of Cardiology and Division of Genetics, Department of Medicine, Boston Children's Hospital Boston, Boston, MA 02115.); Gibbs RA ( Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030); Neel BG ( Princess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7); Kucherlapati R ( Department of Genetics, Harvard Medical School, Boston, MA 02115); |
| Abstract |
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. |
