A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands

Clin Genet. 2014 Apr;85(4):318-27. doi: 10.1111/cge.12187. Epub 2013 Jun 25.


NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro-cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands. A pathogenic mutation was found in 59.3% (1178/1985) of the index patients, mostly de novo (73.8%). The majority of the index patients (64.3%) fulfilled the National Institute of Health NF1 criteria, a pathogenic mutation was found in 80.9% of these patients. Seventy-four percent of the index patients with an NF1 pathogenic mutation and not fulfilling the NF1 criteria is <12 years, in agreement with the fact that some NF1 symptoms appear after puberty. Genotype-phenotype correlations were studied for 527 index patients. NF1 patients with a type 1 microdeletion have a sixfold higher risk of special education vs NF1 patients with an intragenic mutation. No evidently milder NF1 phenotype for patients with a missense mutation was observed. Forty-six prenatal analyses were performed in 28 (2.4%) families, of which 29 (63%) showed heterozygosity for the familial pathogenic mutation. This indicates that there is a need for prenatal NF1 testing.

Keywords: (prenatal) molecular diagnostics; clinical; genetic; neurofibromatosis type 1; the Netherlands.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation*
  • Netherlands
  • Neurofibromatosis 1 / diagnosis*
  • Neurofibromatosis 1 / etiology
  • Neurofibromatosis 1 / genetics*
  • Neurofibromin 1 / genetics
  • Pedigree
  • Young Adult


  • Neurofibromin 1