New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations

Ann Hum Genet. 2016 Jan;80(1):50-62. doi: 10.1111/ahg.12140. Epub 2015 Nov 26.


We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.

Keywords: BRAF; MAP2K1; PTPN11; Rasopathies; cardio-facio-cutaneous syndrome; central Europe; noonan syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cryptorchidism / genetics*
  • DNA Mutational Analysis*
  • Ectodermal Dysplasia / genetics
  • Exons
  • Facies
  • Failure to Thrive / genetics
  • Female
  • Heart Defects, Congenital / genetics
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Noonan Syndrome / genetics*
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Pulmonary Valve Stenosis / genetics*
  • SOS1 Protein / genetics
  • White People / genetics*
  • Young Adult
  • ras Proteins / genetics


  • Intracellular Signaling Peptides and Proteins
  • SHOC2 protein, human
  • SOS1 Protein
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • RIT1 protein, human
  • ras Proteins

Supplementary concepts

  • Cardiofaciocutaneous syndrome