FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate

Clin Genet. 2002 Dec;62(6):470-3. doi: 10.1034/j.1399-0004.2002.620608.x.

Abstract

We report a family showing autosomal-dominant segregation of upper- and lower-eyelid distichiasis (double row of eyelashes) in seven affected relatives over three generations, in addition to below-knee lymphedema of pubertal onset (lymphoedema proecox) in three. Two children had cleft palate in addition to distichiasis, but without the previously reported association with the Pierre-Robin sequence. Other ophthalmologic anomalies included divergent strabismus and early-onset myopia. This family was found to be completely linked to markers mapped to 16q24.3 and thereby proposed to be allelic to the distichiasis-lymphedema syndrome (DL, MIM 153400), although pterygium colli, congenital heart disease, or facial dysmorphism were not features found here. As FOXC2/FKLH14 mutations were found to underlie DL and diverse hereditary lymphedema conditions, this gene was examined by sequence analysis. An out-of-frame deletion (914-921del) was identified and found to segregate with the disease, further highlighting the phenotypic heterogeneity of lymphedema conditions linked to FOXC2 truncating mutations. Whether such heterogeneity is related to genotype-phenotype correlation, a hypothesis not primarily supported by the apparent loss-of-function mechanism of the mutations, or governed by modifying genes, remains to be determined.

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Base Sequence
  • Chromosomes, Human, Pair 16
  • Cleft Palate / genetics
  • DNA-Binding Proteins / genetics*
  • Eyelashes / abnormalities
  • Family Health
  • Female
  • Forkhead Transcription Factors
  • Frameshift Mutation
  • Humans
  • Lymphedema / genetics
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Transcription Factors
  • mesenchyme fork head 1 protein

Associated data

  • OMIM/153400