Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation
| Autor: | Sabine Lüttgen, Christina Evers, Hatip Aydin, Anne-Karin Kahlert, Kerstin Kutsche, Stephan Unkelbach, Stephanie Spranger, María Juliana Ballesta-Martínez, Angela Ovens-Raeder, Bernhard Zabel, Florian von Deimling, Alena Puchmajerová, Andreas Hahn, Vanesa López-González, Robin Satanovskij, Karim Kouz, Christina Lissewski, Sheela Nampoothiri, Maja Hempel, Angelika Riess, Diana Mitter, Pablo Villavicencio-Lorini, Adrian Lieb, Ulrike Issa, Martin Zenker, Heide Seidel |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine congenital heart malformation genetic association genotype phenotype correlation RIT1 gene lymphatic system disease Bioinformatics preschool child Genotype-phenotype distinction genetic variability middle aged Genotype Noonan syndrome Missense mutation genetics gene mutation Genetics (clinical) child clinical article medicine.diagnostic_test adult pedigree RIT1 protein human female germline mutation genetic association study medicine.symptom Ras protein Heart Defects Congenital phenotype oncogenic mutations RASopathy Short stature Article 03 medical and health sciences Germline mutation medicine Humans human gene RASopathies Genetic Association Studies Germ-Line Mutation Genetic testing business.industry missense mutation Cardiomyopathy Hypertrophic hypertrophic cardiomyopathy school child medicine.disease infant clinical feature 030104 developmental biology adolescent RAS-MAPK signaling pathway ras Proteins pathology codon business |
| Zdroj: | Genetics in Medicine. 18:1226-1234 |
| ISSN: | 1098-3600 |
| Popis: | 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. © 2016 American College of Medical Genetics and Genomics. |
| Databáze: | OpenAIRE |
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