A Novel ZRS Mutation Leads to Preaxial Polydactyly Type 2 in a Heterozygous Form and W erner Mesomelic Syndrome in a Homozygous Form

Point mutations in the zone of polarizing activity regulatory sequence ( ZRS ) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly ( PPD ), triphalangeal thumb ( TPT ) or both, a mutation in position 404 of the ZRS causes more severe W erner mesomelic syndrome ( WMS ) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS , 402C>T (AC007097.4:g.105548C>T), that is transmitted through two M exican families with one homozygous individual. The homozygous phenotype for this mutation, WMS , is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD . A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the M exican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation.