MOLECULAR ANALYSIS OF NONDISJUNCTION IN DOWN-SYNDROME PATIENTS WITH AND WITHOUT ATRIOVENTRICULAR SEPTAL-DEFECTS

Background Congenital heart disease is common in Down syndrome patient s, with atrioventricular septal defects accounting for a majority of t he abnormalities. The molecular mechanisms of meiotic nondisjunction r esulting in Down syndrome were studied for associations with the prese nce of atrioventricular septal defects. Methods and Results Twenty hig hly polymorphic chromosome 21 microsatellite markers were used to geno type two groups of patients (group 1: Down syndrome with atrioventricu lar septal defects, n=43; and group 2: Down syndrome without cardiac d efects, n=51) to determine (1) the parental origin of the extra chromo some, (2) the stage of meiotic nondisjunction resulting in the, trisom y, (3) the presence or absence of disomic homozygosity or heterozygosi ty, and (4) the degree of recombination in the nondisjoined chromosome s. The parental origin of the nondisjoined chromosome was maternal in 86.2% of the families, with no significant differences between groups. The most centromeric marker was nonreduced, indicating a meiosis I no ndisjunction in 76.5% of maternally derived trisomies, and reduced, in dicating a meiosis II nondisjunction in 76.9% of paternally derived tr isomies, with no significant differences between groups. There were no significant differences in the proportion of reduced markers al any l ocus between groups. The distribution of the number of crossovers was significantly different between groups (chi(2)=14.12, P<.001), with le ss recombination observed in group 1. Conclusions In Down syndrome pat ients, no association was found between the presence of an atrioventri cular septal defect and the parent of origin, stage of meiotic nondisj unction, or disomic homozygosity or heterozygosity. A significant asso ciation was found between the presence of an atrioventricular septal d efect and reduced frequency of recombination.