누난증후군의 분자유적학적 및 임상적 특징
Molecular and clinical manifestations of Noonan syndrome
Abstract
Objectives: Noonan syndrome (NS) is caused by mutations in genes that encode proteins of the RAS-MAPK signal transduction pathway. The classical form of NS is principally associated with heterozygous missense mutations in several genes. In the present study, we conducted a mutation analysis as well as genotype–phenotype correlations in Korean patients with NS. Methods: The study included 38 NS patients diagnosed by two medical geneticist at the Pusan National University Children’s Hospital, between March 2009 and July 2017. Five genes in the RAS-MAPK pathway associated with NS were analyzed for mutations; the genes were PTPN11, SOS1, RAF1, MEK1, and KRAS. Results: Mutations were detected in 22 patients (56.4%) among 39 patients (15 PTPN11+, 4 RAF1+, 2 SOS1+, 1 MEK1+). Mutation analysis of PTPN11 showed a total of 10 different heterozygous missense variations. Y63C was the most common mutation (26.7%) which is associated with mild phenotype. Patients harboring Q79R, D106A, and N308D mutations showed severe phenotype. Most (78.6%) of PTPN11 mutations were localized in exons 3 or 13. Genetic testing of RAF1 and SOS1 showed a total of 2 different heterozygous missense variations, including novel sequence alterations (V263D, M269R), respectively. Mutation analyses of the entire coding regions of the PTPN11, SOS1, RA1, MEK1, and KRAS genes were negative in 17 patients. In 15 patients with PTPN11 mutations, 11 patients (73.3%) had congenital heart diseases, of which ASD was most frequently observed (80%), and 7 patients (46.6%) had short stature. In 17 patients with PTPN11 negative mutation, 11 patients (64.7%) had congenital heart diseases, of which ASD was most common (63.6%), and 12 patients (70.5%) had short stature. In 4 patients with RAF1 mutations, S257L was the most common mutation (75%) which is associated with severe phenotype. All patients with RAF1 mutations had HCMP of whom 3 patients (75%) had short stature. About 40% of patients with NS showed intellectual disability. About 50% of patients with SOS1 (50%) had congenital heart diseases and short stature, respectively. Conclusions: NS is a genetically and phenotypically heterogeneous. This study expands knowledge of the mutation spectrum in Korean patients with NS.