MUTATIONS IN HUMAN CAUSE LIMB AND CARDIAC MALFORMATION IN HOLT-ORAM SYNDROME

Holt-Gram syndrome is characterized by upper limb malformations and ca rdiac septation defects, Here, we demonstrate that mutations in the hu man TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T -box transcription factor family, A nonsense mutation in TBX5 causes H olt-Gram syndrome in affected members of one family; a TBX5 missense m utation was identified in affected members of another, We conclude tha t TBX5 is critical for limb and heart development and suggest that hap loinsufficiency of TBX5 causes Holt-Gram syndrome.