Trisomic pregnancy and intermediate CGG repeat length at the FMR1 locus

We hypothesized that trisomy arises as a function of the size of the oocyte pool, with risk increased among women with diminished pools. Diminished pools may cause primary ovarian failure, which has been associated with premutation and intermediate CGG repeat length at the Fragile X mental retardation (FMR1) locus. Thus, we hypothesized that the risk of trisomic pregnancy is increased among women with intermediate CGG repeat length on the FMR1 gene.

The analysis drew on data from two hospital-based case-control studies. We compared 207 women with trisomic spontaneous abortions (SAs) to three comparison groups: 82 women with other chromosomally abnormal SAs, 99 women with chromosomally normal SAs and 537 women with live births (LBs), age matched to women with SAs. We defined the length of the CGG repeat in four ways: the biallelic mean, the genotypic mean, the length on allele 2 and the length on allele 1. We analyzed CGG repeat length as a categorical variable. All analyses were adjusted for site, age and ethnicity.

CGG repeat length did not differ significantly between women with trisomic SAs and any of the three comparison groups. For the biallelic mean, the adjusted odds ratio relating trisomy (versus LB controls) to the highest category (35.5-59.5 repeats) versus the modal category (26.5-30.0 repeats) was 1.5 (95% confidence interval (CI): 0.7, 3.1). Comparisons with the two SA control groups also showed increased odds of more repeats among trisomy cases. Results were similar when repeat length was defined by the genotypic mean or by the repeat length on allele 2. For allele 1, the odds of short (9-19) repeat length were lower, but not significantly so, for trisomy cases compared with LB controls. Excluding women with premutations (n= 2) from the analysis yielded an adjusted odds ratio of 1.4 (95% CI: 0.7, 2.9) for the biallelic mean.

Our data are equivocal. The direction of associations is consistent with the hypothesis that repeat length in the intermediate range is associated with trisomy. However, differences between the trisomy cases and the comparison groups are neither large nor statistically significant. Our data rule out odds ratios larger than about 3.