Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

Br J Cancer. 2008 Jan 29;98(2):474-9. doi: 10.1038/sj.bjc.6604156. Epub 2007 Dec 18.

Abstract

Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomes, Human, Pair 22
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Family*
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Humans
  • Infant
  • Inheritance Patterns*
  • Male
  • Microsatellite Repeats / genetics
  • Pedigree
  • Penetrance*
  • Rhabdoid Tumor / genetics*
  • Rhabdoid Tumor / mortality
  • SMARCB1 Protein
  • Sex Characteristics
  • Survival Analysis
  • Syndrome
  • Time Factors
  • Transcription Factors / genetics*

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors