The cause of non-disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non-disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non-disjunction involves increased recombination that is largely restricted to proximal 21q. Thus, while absence of a proximal recombination appears to predispose to non-disjunction in MI, the presence of a proximal exchange predisposes to non-disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non-disjunction results from events occurring in meiosis I.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.

We conducted a large population-based survey of fragile X (FRAXA) syndrome in ethnically diverse metropolitan Atlanta. The eligible study population consisted of public school children, aged 7-10 years, in special education-needs (SEN) classes. The purpose of the study was to estimate the prevalence among whites and, for the first time, African Americans, among a non-clinically referred population. At present, 5 males with FRAXA syndrome (4 whites and 1 African American), among 1,979 tested males, and no females, among 872 tested females, were identified. All males with FRAXA syndrome were mentally retarded and had been diagnosed previously. The prevalence for FRAXA syndrome was estimated to be 1/3,460 (confidence interval [CI] 1/7,143-1/1,742) for the general white male population and 1/4, 048 (CI 1/16,260-1/1,244) for the general African American male population. We also compared the frequency of intermediate and premutation FRAXA alleles (41-199 repeats) and fragile XE syndrome alleles (31-199 repeats) in the SEN population with that in a control population, to determine if there was a possible phenotype consequence of such high-repeat alleles, as has been reported previously. No difference was observed between our case and control populations, and no difference was observed between populations when the probands were grouped by a rough estimate of IQ based on class placement. These results suggest that there is no phenotype consequence of larger alleles that would cause carriers to be placed in an SEN class.

Over 300 cases of trisomy 21 were analyzed to characterize the causes of maternal non-disjunction and to evaluate the basis for maternal age-dependent trisomy 21. We confirmed the observation that recombination along 21q is reduced among non-disjoined chromosomes 21 and further demonstrated that the alterations in recombination are restricted to meiosis I origin. Analysis of the crossover distribution indicates that reduction in recombination is not due simply to failure of pairing and/or absence of recombination in a proportion of cases. Instead, we observed an increase in both zero- and one-exchange events among trisomy 21-generating meioses suggesting that an overall reduction in recombination may be the underlying cause of non-disjunction. Lastly, we observed an age-related reduction in recombination among the meiosis I cases, with older women having less recombination along 21q than younger women. Thus, reduced genetic recombination may be responsible, at least in part, for the association between advancing maternal age and trisomy 21.