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

Abstract

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.

Islet Autoimmunity in Children With Down’s Syndrome

“…Down's syndrome. Blood samples were taken from 30 nondiabetic schoolaged children with Down's syndrome (15 male and 15 female, 4 -21 years of age) during routine thyroid screening in the area covered by the Gloucestershire Health Authority, U.K. Aliquots of DNA samples from 83 children with Down's syndrome had been collected as part of a study of congenital heart disease in Down's syndrome (15). Samples were also available (109 DNA and 106 serum) for analysis from a population-based study of children with Down's syndrome in Manchester, the Hester Adrian Research Centre cohort (16).…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…The COL-α1 (VI) and -α2 (VI) chains are encoded by genes located on Hsa21 and their overexpression has been associated with atrioventricular canal defects in Down syndrome [133,134]. The α3 (VI) chain is encoded by the COL6A3 located at chromosome 2, and individuals with Down syndrome who have single nucleotide polymorphisms in COL6A3 are at increased risk of muscle hypotonia and CHD [135].…”

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

“…Distinguishing whether insulin deficiency in these young children is caused by accelerated autoimmunity or an alternative mechanism, such as a b-cell secretary deficit, could have consequences for treatment or provide insights into a more aggressive autoimmune process in children with DS. Aliquots of DNA samples from 83 children with DS had been collected as controls for a study of congenital heart disease in DS (13). DNA samples (n = 109) were also available for analysis from a population-based study of children with DS in Manchester, U.K. (14).…”