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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.

Original publication




Journal article


Hum Mol Genet

Publication Date





2417 - 2423


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