title: Spectrum of mutations in Noonan syndrome and their correlation with phenotypes.
abstract: OBJECTIVE
  To investigate mutation spectrums and their correlations to phenotypes in Noonan syndrome (NS) and NS-related disorders that share functional alterations of the Ras-mitogen-activated protein kinase pathway.
  
  
  METHODS
  Clinical characteristics and genotypes of 10 previously known and 2 candidate genes, SPRY1-4 and SPRED1, were investigated in 59 patients with NS, 17 with cardiofaciocutaneous syndrome, 5 with Costello syndrome, and 2 with LEOPARD syndrome.
  
  
  RESULTS
  PTPN11 (39.0%), SOS1 (20.3%), RAF1 (6.8%), KRAS (5.1%), and BRAF (1.7%) mutations were identified in NS; BRAF (41.2%), SHOC2 (23.5%), and MEK1 (5.9%) mutations in cardiofaciocutaneous syndrome; and HRAS and PTPN11 mutations in Costello syndrome and LEOPARD syndrome, respectively. No additional mutations were identified in 28.9% of NS and 35.3% of cardiofaciocutaneous syndrome. Functional characterizations of 2 RAF1 novel variants, p.P261T and p.S259T, and one SOS1 variant, p.K170E, showed enhanced activity of Ras-mitogen-activated protein kinase pathway. Normal stature was frequent in SOS1 mutations, hypertrophic cardiomyopathy in RAF1, and developmental delay in RAF1, BRAF, or SHOC2 mutations.
  
  
  CONCLUSIONS
  By identifying genotype-phenotype correlations, our study highlights the role of molecular genetic testing in the process of differential diagnosis of NS and NS-related disorders. Pathophysiologies that underlie these correlations are needed to be investigated in terms of their effects on Ras-mitogen-activated protein kinase pathway.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Jin
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult