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

TitleNext-generation sequencing identifies rare variants associated with Noonan syndrome.
Publication TypeJournal Article
Year of Publication2014
AuthorsChen, P-C, Yin, J, Yu, H-W, Yuan, T, Fernandez, M, Yung, CK, Trinh, QM, Peltekova, VD, Reid, JG, Tworog-Dube, E, Morgan, MB, Muzny, DM, Stein, L, McPherson, JD, Roberts, AE, Gibbs, RA, Neel, BG, Kucherlapati, R
JournalProc Natl Acad Sci U S A
Date Published2014 Aug 05
KeywordsAlleles, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mutation, Neurofibromin 1, Noonan Syndrome, ras Proteins

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.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID25049390
PubMed Central IDPMC4128129
Grant ListU54HG003273 / HG / NHGRI NIH HHS / United States
/ CAPMC / CIHR / Canada
U54 HG003273 / HG / NHGRI NIH HHS / United States
HL 083272 / HL / NHLBI NIH HHS / United States
R37CA49132 / CA / NCI NIH HHS / United States

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