PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome.
After 2006, germline mutations in the KRAS, SOS1, and RAF1 genes were reported to cause Noonan syndrome (NS), in addition to the PTPN11 gene, and now we can find the etiology of disease in approximately 60-70% of NS cases. The aim of this study was to assess the correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with NS. We found disease-causing mutations in 30 (50.8%) patients, which were located in the PTPN11 (27.1%), SOS1 (16.9%), KRAS (1.7%), and RAF1 (5.1%) genes. Three novel mutations (T59A in PTPN11, K170E in SOS1, S259T in RAF1) were identified. The patients with PTPN11 mutations showed higher prevalences of patent ductus arteriosus and thrombocytopenia. The patients with SOS1 mutations had a lower prevalence of delayed psychomotor development. All patients with RAF1 mutations had hypertrophic cardiomyopathy. Typical facial features and auxological parameters were, on statistical analysis, not significantly different between the groups. The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS-MAPK pathway.
Ko
Jung Min
JM
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Kim
Jae-Min
JM
Genome Research Center for Birth defects and Genetic Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Kim
Gu-Hwan
GH
Medical Genetics Clinic and Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Yoo
Han-Wook
HW
Department of Pediatrics, Medical Genetics Clinic and Laboratory, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-2dong, Songpa-gu, Seoul, 138-736, South Korea. hwyoo@amc.seoul.kr.
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007723:Korea / Q000453:epidemiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020837:SOS1 Protein / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D020837:SOS1 Protein; D019908:Proto-Oncogene Proteins c-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins