HOLT-ORAM SYNDROME IS CAUSED BY MUTATIONS IN TBX5, A MEMBER OF THE BRACHYURY (T) GENE FAMILY

Holt-Gram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mo use Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a p remature stop codon in the TBX5 gene product. Tissue in situ hybridiza tion studies on human embryos from days 26 to 52 of gestation reveal e xpression of TBX5 in heart and limb. consistent with a role in human e mbryonic development.