A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb

Hum Mol Genet. 2008 Aug 15;17(16):2417-23. doi: 10.1093/hmg/ddn141. Epub 2008 May 7.


A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Chromosomes, Human, Pair 7 / genetics
  • Cohort Studies
  • Enhancer Elements, Genetic*
  • Extremities / embryology
  • Extremities / growth & development*
  • Female
  • Gene Expression Regulation, Developmental*
  • Genetic Linkage
  • Hand Deformities, Congenital / embryology
  • Hand Deformities, Congenital / genetics*
  • Haplotypes
  • Hedgehog Proteins / genetics*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microsatellite Repeats
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Polydactyly / embryology
  • Polydactyly / genetics*
  • Sequence Alignment


  • Hedgehog Proteins
  • SHH protein, human