The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration

Orphanet J Rare Dis. 2014 Jan 23:9:12. doi: 10.1186/1750-1172-9-12.


Background: WWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers. It is therefore considered a tumor suppressor gene, but its direct implication in cancerogenesis remains controversial.

Methods and results: By whole-exome sequencing, we identified a homozygous WWOX nonsense mutation, p.Arg54*, in a girl from a consanguineous family with a severe syndrome of growth retardation, microcephaly, epileptic seizures, retinopathy and early death, a phenotype highly similar to the abormalities reported in lde/lde rats with a spontaneous functional null mutation of Wwox. As in rats, no tumors were observed in the patient or heterozygous mutation carriers.

Conclusions: Our finding, a homozygous loss-of-function germline mutation in WWOX in a patient with a lethal autosomal recessive syndrome, supports an alternative role of WWOX and indicates its importance for human viability.

Publication types

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

MeSH terms

  • Epilepsy / genetics*
  • Humans
  • Infant
  • Microcephaly / genetics*
  • Mutation
  • Oxidoreductases / genetics
  • Retinal Degeneration / genetics
  • Tumor Suppressor Proteins / genetics
  • WW Domain-Containing Oxidoreductase


  • Tumor Suppressor Proteins
  • Oxidoreductases
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human