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

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.