The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte

Abstract

Altered patterns of recombination on 21q have long been associated withthe nondisjunction chromosome21within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the first time genotyped the gene MCM9, a candidate gene for recombination regulation and DNA repair in mothers with or without children with Down syndrome. In our approach, we identified the location of recombination on the maternal chromosome 21 using short tandem repeat markers, then stratified our population by the origin of meiotic error and age at conception. We observed that twenty-five out of forty-one single nucleotide polymorphic sites within MCM9 exhibited an association with meiosis I error (N = 700), but not with meiosis II error (N = 125). This association was maternal age-independent. Several variants exhibited aprotective association with MI error, some were neutral. Maternal age stratified characterization of cases revealed that MCM9 risk variants were associated with an increased chance of reduced recombination on 21q within oocytes. The spatial distribution of single observed recombination events revealed no significant change in the location of recombination among women harbouring MCM9 risk, protective, or neutral variant. Additionally, we identified a total of six novel polymorphic variants and two novel alleles that were either risk imparting or protective against meiosis I nondisjunction. In silico analyses using five different programs suggest the risk variants either cause a change in protein function or may alter the splicing pattern of transcripts and disrupt the proportion of different isoforms of MCM9 products within oocytes. These observations bring us a significant step closer to understanding the molecular basis of recombination errors in chromosome 21 nondisjunction within oocytes that leads to birth of child with Down syndrome.

Molecular functions of MCM8 and MCM9 and their associated pathologies

“… 78 Birth of child with Down syndrome Pal et al. 79 Infertility, female AlAsiri et al., Tenenbaum-Rakover et al., Dou et al., Desai et al., Bouali et al., Zhang et al., Heddar et al., Wang et al., Jin et al., Tucker et al. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Desai et al., Alvarez-Mora et al., Fauchereau et al., França et al., Goldberg et al., Guo et al., Liu et al., Shen et al., Turkyilmaz et al., Wood-Trageser et al., Yang et al., and Jolly et al.…”

“…For example, Pal et al. 79 identified a multitude of MCM9 polymorphisms in the genomes of women with a Down syndrome child (OMIM 190685 ), hypothesizing that the variants may increase the chance of a child with Down syndrome because of their association with the recombination and nondisjunction of chromosome 21 at meiosis I stage of oogenesis in a maternal age-independent manner. Moreover, Bally et al.…”

Incidence of Down Syndrome by maternal age in Chinese population

“…They are also more likely to be sleep-deprived, have an imbalanced diet to control body weight. Recent studies have identified some genetic predispositions (just as consanguineous marriage, maternal telomere length, maternal MCM9 polymorphisms, maternal Presenilin-1 and Apolipoprotein E polymorphisms) of women that may cause nondisjunction and Down syndrome birth at younger age ( Ray et al, 2016 ; Bhaumik et al, 2017 ; Ray et al, 2018 ; Pal et al, 2021 ). These are age-independent risk factors.…”