Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene

Am J Hum Genet. 2010 Jul 9;87(1):146-53. doi: 10.1016/j.ajhg.2010.06.008.


Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Diseases, Developmental / complications
  • Bone Diseases, Developmental / genetics*
  • Bone Neoplasms / complications
  • Bone Neoplasms / genetics*
  • Child, Preschool
  • Contractile Proteins / genetics*
  • Female
  • Fibroma / complications
  • Fibroma / genetics*
  • Filamins
  • Genetic Association Studies
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microfilament Proteins / genetics*
  • Mutation
  • Neoplasm Recurrence, Local
  • Pedigree
  • Pigmentation Disorders / complications
  • Pigmentation Disorders / genetics*
  • Skin Pigmentation


  • Contractile Proteins
  • Filamins
  • Microfilament Proteins