ArticleProceedings of the National Academy of Sciences of the United States of America2014
Next-generation sequencing identifies rare variants associated with Noonan syndrome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.
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Who cites it
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 184 citations in OpenAlex.
- Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels.Genome medicine · 2019Pooled it
- Rigosertib Reverses Hypertrophic Cardiomyopathy in Noonan Syndrome.Circulation · 2026Article
- Clinical and Molecular Portraits of Pediatric RASopathies: A Study of 118 Genotype-Confirmed Cases.Clinical genetics · 2026Article
- Unveiling the Prevalence and Surgical Burden of Neurocristopathies: A Scoping Review and Statistical Analysis.Research square · 2026Article
- E3 Ubiquitin Ligase Mind Bomb 1 is a Novel Negative Regulator of Tumor-Suppressive BMP Signaling.Cancer research communications · 2026Article
- Molecular Diagnosis and Phenotypic Variability of Noonan Syndrome: Experience from a Romanian Multicenter Study.Diagnostics (Basel, Switzerland) · 2026Article
- Article
- Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.Molecular syndromology · 2026Article
- Molecular characterization of individuals with RASopathies: Spectrum of genetic variants in a large Indian cohort.Journal of genetics · 2026Article
- Expanding the Genetic Landscape of RASopathies: Significance of IncludingMolecular syndromology · 2025Article
- Advancing edge-based clustering and graph embedding for biological network analysis: a case study in RASopathies.Briefings in bioinformatics · 2025Article
- Genetic factors underlying Mandibular prognathism: insights from recent human and animal studies.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma.Biology direct · 2025Article
- Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.European journal of pediatrics · 2024Article
- RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.Disease models & mechanisms · 2024Review
- Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2024Article
- Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion.Trends in immunology · 2023Review
- Craniosynostosis, inner ear, and renal anomalies in a child with complete loss ofJournal of medical genetics · 2023Article
- Neurofibromatosis-Noonan syndrome and growth deficiency in an Iranian girl due to a pathogenic variant in NF1 gene.Human genomics · 2023Article
- Diverse Clinical Manifestations of Cardiofaciocutaneous Syndrome Type 3 in Two Patients from South East Asia.Molecular syndromology · 2023Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 9 institutions in 3 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.