A GENE FOR HOLT-GRAM SYNDROME MAPS TO THE DISTAL LONG ARM OF CHROMOSOME-12

Holt-Gram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associat ed malformations of the upper limbs (radial ray). Here, we report on t he mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21-qter) by linkage analysis in nine informative families (Z(ma x)=6.81 at theta=0 at the D12S354 locus). Also, multipoint linkage ana lysis places the HOS gene within the genetic interval between D12S84 a nd D12S79 (multipoint lodscore in log base 10=8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the mol ecular mechanisms that govern heart septation in the early stages of e mbryogenesis.