PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations

Am J Med Genet A. 2006 Jun 15;140(12):1297-301. doi: 10.1002/ajmg.a.31278.


Neuroblastoma (NB) is an embryonal tumor originating from neural crest cells and is one of the most common solid tumors of childhood. Recently, constitutional mutations in PHOX2B have been shown to confer an increased risk of NB. To date, mutations predisposing to neural crest tumors have been reported in 20 individuals from 16 families. These families included additional clinical features such as Hirschsprung (HSCR) disease or congenital central hypoventilation syndrome, either in the index case or relatives. The contribution of PHOX2B mutations to NB cases without additional features is unclear. To address this we sequenced PHOX2B in constitutional DNA from 86 individuals with non-syndromic NB (4 cases had a family history of NB). We identified two mutations, 600delC, a frameshift mutation in an individual with isolated, unifocal NB and G197D, a missense mutation that was present in a family with multiple individuals with NB but no evidence of autonomic dysfunction. These data demonstrate that PHOX2B mutations are a rare cause of non-syndromic NB. The mutations we identified are outside the domains typically mutated in PHOX2B syndromes. This provides further evidence that the underlying PHOX2B mutational mechanism influences tumor risk and suggests that the position of missense mutations may influence the resulting phenotype.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genetic Variation
  • Genotype*
  • Hirschsprung Disease / genetics
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / genetics*
  • Humans
  • Hypoventilation / genetics
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Neuroblastoma / genetics*
  • Pedigree
  • Phenotype*
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • United Kingdom / epidemiology


  • Homeodomain Proteins
  • NBPhox protein
  • Transcription Factors