Aberrant meiotic recombination mediated by maternal RNF212, PRDM9, and SPO11 variants increases risk of chromosome 21 nondisjunction and Down syndrome birth

Abstract Background The cause of chromosome 21nondisjunction and subsequent Down syndrome birth are not all stochastic and there are certain genetic predispositions for meiotic recombination anomalies that increase the risk of trisomy21 conception. This entire etiology is complicated, enigmatic and needs to be addressed with explicit experimental approach. Result We genotyped recombination regulators RNF212 , PRDM9 and SPO11 from the genome of women having trisomy 21 child stratifying them according to their age at conception and origin of meiotic errors. Out of 34 variants nineteen unique sequence alterations exhibited association with meiosis I error ( N = 700), while four exhibited association with meiosis II error ( N = 125) and this association was maternal age independent. These risk variants were found associated with reduced recombination on long arm of chromosome 21 among the women of all age groups. In addition, variants of RNF212 and PRDM9 exhibited association with the altered position of single recombinant event on the nondisjoined chromosome 21. Conclusion Our novel results revealed that the risk variants of RNF212 , PRDM9 , but not the SPO11 may reduce recombination on chromosome 21 and cause altered placement of single recombinant events on chromosome 21 and make the homologues vulnerable for nondisjunction. The variant of RNF212 increase the risk of peri-telomeric single recombination that in turn makes the chromosome susceptible to meiosis I nondisjunction in maternal age-independent manner. On the other hand variants of PRDM9 increase risk of pericentromeric recombination on chromosome that nondisjoined at meiosis II in maternal age-dependent manner and also elevate the chance of pertelomeric exchange that increase the risk of meiosis I nondisjunction in maternal age independent manner. We for the first time provide evidence that some important recombination regulators in human oocyte, when carry risk variants, increase chance anomalous positioning of chiasma on the pairing homologues that reduces frequency of recombination and challenges faithful segregation of the chromosomes. This underpins the aneuploidy birth.