Heterotrisomy, a significant contributing factor to ventricular septal defect associated with Down syndrome?

Down syndrome (DS; trisomy 21) is associated with a wide range of variable clinical features, one of the most common being congenital heart defects (CHD). We used molecular genetic techniques to study the inheritance of genes on chromosome 21 in children with DS and CHD. Polymorphic markers on the long arm of chromosome 21 were analysed in 99 families who had a child with DS. Of these, 60 children had a CHD and 39 children had no CHD. Heterotrisomy describes the inheritance of an allele from each of three different grandparents. In some cases heterotrisomy will involve the inheritance of three different alleles. Heterotrisomic regions were defined as those showing retention of non-disjoining parental heterozygosity at polymorphic loci in the non-disjoined chromosomes of children with DS. Using polymorphic non-coding markers, we identified a consistent 9.6-cM minimum region (D21S167-HMG14) of heterotrisomy in children with DS and ventricular septal defect (VSD). Comparing individuals with DS and VSD to all others with DS (those either with no CHD or with any other CHD combined) shows the individuals with DS and VSD to have significantly more non-reduction or heterotrisomy in this region (P=0.006, Fisher's exact test, two-tailed). We postulate that heterotrisomy for a gene or genes in this region is a contributing factor to the pathogenesis of VSD in trisomy 21 either through the presence of three different specific alleles or through the presence of specific combinations of alleles.

Human COL6A1: genomic characterization of the globular domains, structural and evolutionary comparison with COL6A2.

The alpha1(VI) and alpha2(VI) chains of type VI collagen (nonfibrillar) are highly similar and are encoded by single-copy genes in close proximity on human Chromosome (Chr) 21q22.3, a gene-rich region that has proved refractory to cloning. For the alpha1(VI) chain, only the regions encoding the triple-helical and the promoter have been characterized hitherto.To facilitate our study of the role of this gene in the phenotype of Down syndrome, we have cloned and sequenced the amino- and carboxyl-terminal globular domains of COL6A1. The amino-terminal domain consists of seven exons and the carboxyl-terminal globular domain of nine exons. Together with the exons of the triple-helical domain, COL6A1 is encoded by a total of 36 exons spanning approximately 30 kb. Comparison of the genomic organization of COL6A1 and COL6A2 revealed that despite the similarity within their triple-helical domains, the intron-exon structures of their globular domains differ markedly. Conservation is limited to the exons encoding amino acids immediately adjacent to the triple-helical region, including the cysteine residues essential for the structure of mature collagen VI. The intron-exon structures of these two genes are highly similar to the collagen VI genes of chicken. These data suggest that COL6A1 and COL6A2 arose from a gene duplication before the divergence of the reptilian and mammalian lineages.