Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
27101134
DOI
10.1038/gim.2016.32
PII: S1098-3600(21)01412-X
Knihovny.cz E-resources
- MeSH
- Phenotype MeSH
- Genetic Association Studies MeSH
- Genotype MeSH
- Cardiomyopathy, Hypertrophic genetics pathology MeSH
- Humans MeSH
- Noonan Syndrome genetics pathology MeSH
- ras Proteins genetics MeSH
- Pedigree MeSH
- Heart Defects, Congenital genetics pathology MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ras Proteins MeSH
- RIT1 protein, human MeSH Browser
PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited. METHODS: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed. RESULTS: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent. CONCLUSION: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.
Centre for Pediatric and Adolescent Medicine University Hospital Freiburg Freiburg Germany
Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain
Darmstädter Kinderkliniken University Hospital Frankfurt Frankfurt Germany
Department of Child Neurology Justus Liebig University Giessen Germany
Department of Medical Genetics Medical Faculty Namık Kemal University Tekirdag Turkey
Facharztzentrum Pädiatrie und Humangenetik Martin Luther Universität Halle Wittenberg Halle Germany
Institut für Humangenetik Klinikum rechts der Isar Technische Universität München München Germany
Institut für Klinische Genetik TU Dresden Dresden Germany
Institute of Human Genetics Heidelberg University Heidelberg Germany
Institute of Human Genetics Ludwig Maximilian University Munich Germany
Institute of Human Genetics Martin Luther University Halle Wittenberg Halle Germany
Institute of Human Genetics University Hospital Leipzig Leipzig Germany
Institute of Human Genetics University Hospital Magdeburg Magdeburg Germany
Institute of Human Genetics University Medical Center Hamburg Eppendorf Hamburg Germany
Institute of Medical Genetics and Applied Genomics University of Tuebingen Tuebingen Germany
Praxis für Humangenetik Bremen Germany
Praxis für Humangenetik München Germany
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