Next-generation sequencing identifies rare variants associated with Noonan syndrome.

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.

• Authors: Peng-Chieh Chen, Jiani Yin, Hui-Wen Yu, Tao Yuan, Minerva Fernandez, Christina K Yung, Quang M Trinh, Vanya D Peltekova, Jeffrey G Reid, Erica Tworog-Dube, Margaret B Morgan, Donna M Muzny, Lincoln Stein, John D McPherson, Amy E Roberts, Richard A Gibbs, Benjamin G Neel, Raju Kucherlapati
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 31 Pg. 11473-8 (Aug 05 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25049390 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Neurofibromin 1
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• RIT1 protein, human
• ras Proteins

Topics

• Alleles
• Genetic Association Studies
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• MAP Kinase Kinase 1 (genetics)
• MAP Kinase Signaling System (genetics)
• Mutation (genetics)
• Neurofibromin 1 (genetics)
• Noonan Syndrome (genetics)
• ras Proteins (genetics, metabolism)