Dear Colleagues,

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant tumor predisposition syndromes. Clinical diagnosis of this condition relies on specific diagnosis criteria outlined in the National Institutes of Health consensus development conference in 1987. The broad phenotypic spectrum and age-dependent symptoms make clinical diagnosis challenging, particularly in young individuals. NF1 is caused by heterozygous loss-of-function mutations of the tumor suppressor NF1 (Neurofibromin 1). The mutation rate at the NF1 locus is one of the highest reported in any human disorder. This observation is reflected in the finding that almost 50% of all NF1 patients exhibit a de novo NF1 mutation. A huge number of different pathogenic NF1 mutations have been reported. The absence of genotype–phenotype correlation demonstrates the minor role of the NF1 gene in the great variability of NF1 clinical expression, with the rare exceptions of (i) missense mutations in codons 844-848 and Arg1809, one short in-frame deletion (p.Met992del), and (ii) the recurrent large deletions of the NF1 locus. Evidence of modifier genes was provided by animal models and intrafamilial phenotypic correlations. Genetic heterogeneity in NF1 has been evidenced by the identification of pathogenic mutations in the SPRED1 gene causing an NF1 phenocopy, the so-called Legius syndrome. NF1 mutation detection and interpretation are challenging owing to the large size of the gene, the existence of multiple highly identical pseudogenes, the lack of mutational hotspots, and the complex mutational spectrum. Targeted next-generation sequencing (NGS) can be applied to the accurate identification of NF1 and SPRED1 variants and copy number alterations (CNAs), and to establish the unambiguous diagnosis of NF1 or Legius syndrome, particularly in mosaicism presentations of low-frequency mutations, and in uncertain clinical presentations.

This Special Issue of Genes dedicated to neurofibromatosis type 1 genetics welcomes reviews and original papers covering recent genetic research on NF1 molecular diagnosis and genetic counselling, and on the effect of mutations and modifier genes on NF1-related phenotypes; case reports highlighting testing approaches that can be utilized in several clinical scenarios may also be considered

Dr. Eric Pasmant
Guest Editor

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• NF1
• SPRED1
• neurofibromatosis type 1
• Legius syndrome
• mosaicism
• genotype-phenotype correlation
• molecular diagnosis