title: Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy.
abstract: OBJECTIVE
  Molecular characterization of congenital heart diseases now includes the not infrequent dysmorphic Noonan syndrome. A study of 6 genes of the RAS-MAPK pathway in Spanish patients is presented: the impact of heart disease, clinical expressivity, and diagnostic yield are investigated.
  
  
  METHODS
  The study included 643 patients (and 182 family members) diagnosed by dysmorphologists, cardiologists, and pediatric endocrinologists from 74 tertiary hospitals. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, KRAS and HRAS focused on exons carrying recurrent mutations accounting for 80% to 95% of previously described mutations.
  
  
  RESULTS
  Mutations were detected in 230 patients (91 women and 139 men) in 200 (31%) families (172 PTPN11+, 14 SOS1+, 9 RAF1+, 5 BRAF+). There was specific reference to the heart defect suffered in 156 index cases: 103 patients had shown pulmonary stenosis, 12 pulmonary stenosis with hyperthrophic cardiomyopathy, 18 hypertrophic cardiomiopathy, and 14 other cardiopathies; heart disease was absent in 9 index cases. Heart disease had not been documented in 23 of 30 family members with positive genotype and compatible clinical signs. Diagnostic yield was higher (P=.016) for samples from some centers (53%; 14/32) and even from certain professionals (64%; 9/14; P=.019). Characterization rate was 18% in patients for whom clinical data were not available. Genotyping led to a more precise diagnosis in 26 patients.
  
  
  CONCLUSIONS
  Most patients (94%) with a positive genotype had known congenital heart disease, 79% pulmonary stenosis and 12% hyperthrophic cardiomyopathy. Cardiopathy had not been documented in 76% of family members carrying the mutation. Molecular study is a useful tool in these syndromes but a more rigorous clinical diagnosis should be intended as well.
authors.affiliation: Laboratorio de Diagnóstico Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. bezquieta.hgugm@salud.madrid.org
authors.forename: Begoña
authors.initials: B
authors.lastname: Ezquieta
authors.forename: José L
authors.initials: JL
authors.lastname: Santomé
authors.forename: Atilano
authors.initials: A
authors.lastname: Carcavilla
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén-Navarro
authors.forename: Antonio
authors.initials: A
authors.lastname: Pérez-Aytés
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez del Pozo
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaur
authors.forename: Emilia
authors.initials: E
authors.lastname: Castillo
authors.forename: Milagros
authors.initials: M
authors.lastname: Alonso
authors.forename: Teresa
authors.initials: T
authors.lastname: Vendrell
authors.forename: Alfredo
authors.initials: A
authors.lastname: Santana
authors.forename: Enrique
authors.initials: E
authors.lastname: Maroto
authors.forename: Liliana
authors.initials: L
authors.lastname: Galbis
mesh_terms: D000293:Adolescent; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002648:Child; D004476:Ectodermal Dysplasia / Q000235:genetics*; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics*; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D011666:Pulmonary Valve Stenosis / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics
chemical_list: D020837:SOS1 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11