Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors.

Purpose: The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome. Methods: Between 2000 and 2004, six sites collected DNA, clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects. Results: Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40 -2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32-3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30 -0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects. Conclusions: Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome.Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects. The National Down Syndrome Project (NDSP) seeks to investigate the etiology and phenotypic consequences of trisomy 21 Down syndrome (DS). 1 Aside from the universal findings of mental retardation and hypotonia, congenital heart defects (CHDs) are arguably the most important clinical sequelae of an extra chromosome 21. In 1998 the Atlanta Down syndrome Project (ADSP), a forerunner of the NDSP, reported that 41% of newborns with DS were born with one or more major heart defects, including atrioventricular septal defect (AVSD), secundum atrial septal defect (ASDII), ventricular septal defect (VSD), and tetralogy of Fallot (TOF). 2 Findings from the ADSP and other recent population-based studies of DS and CHDs 2-5 are summarized in Table 1.With the birth prevalence of major DS-associated CHDs well established by multiple studies using modern diagnostic methods, attention can now be directed toward understanding the etiology of these defects. Not only do infants with DS have a higher rate of CHDs than do infants without DS, but one defect, the AVSD, is particularly characteristic. To understand the etiology of CHDs in DS and of AVSD specifically, both genetic and environmental determinants must be explored. For example, several recent reports have suggested that the distribution of CHDs in DS varies by ethnicity (race/ethnicity), 6 -13 but most population-based studies have not had broad ethnic representation (Table 1). Drawing on our experience with the ADSP, we designed the multicenter NDSP to explore possible CHD risk factors singly and in combination. The NDSP is one of the largest population-based studies of CHDs in DS and the first to assemble clinical, demographic, a...

This exceptional compilation of questionnaire, clinical, and molecular data makes the NDSP a unique resource for ongoing studies of the etiology and phenotypic consequences of trisomy 21. The combined approach increases study power by defining subgroups of cases by the origin of nondisjunction. This report describes the design and successful implementation of the

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine β-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r2≥0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over-transmitted to cases with AVSD (P = 0.05) and under-transmitted to controls (P = 0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS.

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.