Association between telomere length and chromosome 21 nondisjunction in the oocyte

Abstract

Chromosome 21 nondisjunction in oocytes is the most common cause of trisomy 21, the primary chromosomal abnormality responsible for Down syndrome (DS). This specific type of error is estimated to account for over 90% of live births with DS, with maternal age being the best known risk factor for chromosome 21 nondisjunction. The loss of telomere length and the concomitant shortening of chromosomes is considered a biological marker for aging. Thus, we tested the hypothesis that mothers who had a maternal nondisjunction error leading to a live birth with DS (N=404) have shorter telomeres than mothers with live births without DS (N=42). In effect, our hypothesis suggests that mothers of children with DS will appear “biologically older” as compared to the mothers of euploid children. We applied a quantitative PCR assay to measure the genome-wide relative telomere length in order to test this hypothesis. The results of our study support the hypothesis that young mothers of DS babies are “biologically older” than mothers of euploid babies in the same age group and supports telomere length as a biomarker of age and hence risk for chromosome nondisjunction.

Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length

“…In a previous study from our group (Albizua et al, ), we found a similar pattern of telomere length among women who had a child with trisomy 21 derived from a nondisjunction error in the oocyte compared with controls. In that study, we suggested that the reduced slope in the age‐related pattern reflected a biologically older stage; the telomeres were already shorter at the youngest ages studied and then declined less.…”

Increased MTHFR promoter methylation in mothers of Down syndrome individuals

“…One of the major limits for the study of the molecular mechanisms leading to chromosome 21 malsegregation is the unavailability of human egg cells from MDS, so that most of the studies aimed at linking folate metabolism to chromosome 21 malsegregation have been performed with surrogate cells and tissues, including peripheral lymphocytes [3][4][5][6][7]. In this regard, in vitro studies in human lymphocytes have shown that folate restriction induces chromosome 21 aneuploidy [31,32].…”

“…Similarly, the studies performed so far in peripheral lymphocytes from MDS revealed that those cells are characterized by several markers of genome instability and premature ageing, including an increased frequency of micronuclei, short telomeres, and global changes in DNA methylation [3][4][5][6][7][8][9][10]. Those biomarkers could be indicators of altered pathways, such as impaired folate metabolism, accounting for an increased risk to give birth to a DS child in young age or to develop age-related neurodegenerative diseases later in life [3][4][5][6][7][8][9][10].…”

“…The micronucleus assay revealed that young mothers of DS individuals (MDS) have an increased susceptibility to chromosome damage and malsegregation events in peripheral lymphocytes than control mothers [3][4][5][6]. Additionally, the analysis of telomere lenght in peripheral lymphocytes showed that women who conceived a DS child before 35 years of age have shorter telomeres than matched control mothers, suggesting that they might be "biologically older" than mothers of euploid babies in the same age group [7]. Interestingly, young MDS were also found to have a five-fold increased risk to develop Alzheimer's disease later in life [8,9].…”

Gene Polymorphisms That Predispose Women for Down Syndrome Child Birth

“…With subsequent analyses of maternal molecular age, it has been proved that mothers of Down syndrome baby have shorter average telomere length than do the mothers of same chronological age and have euploid healthy baby [4,5]. The authors proposed that a group of women may suffer from advanced molecular and genetic aging and intuitively carry predisposition for NDJ.…”