Gene variants identified that influence the risk of aneuploidy

Variants in maternal genes that increase the risk of aneuploidy have been identified.

Aneuploidy occurs when cells have the incorrect number of chromosomes, and is one of the leading causes of early pregnancy loss. These chromosome errors most frequently arise during meiosis, the specialised cell division which produces eggs and sperm. Human eggs are particularly vulnerable because meiosis starts before birth and is halted for many years, increasing the chance of chromosome errors as women age. The findings of the study, published in Nature, show that inherited genetic variation can influence the risk of chromosome errors occurring.

'This work provides the clearest evidence to date of the molecular pathways through which variable risk of chromosomal errors arises in humans,' said Dr Rajiv McCoy, senior author of the study and an associate professor at Johns Hopkins University in Baltimore, Maryland. 'These insights deepen our understanding of the earliest stages of human development and open the door for future advances in reproductive genetics and fertility care.'

The research team analysed genetic and reproductive data from almost 23,000 sets of biological parents undergoing fertility treatment, studying more than 139,000 embryos created using IVF. By studying results from preimplantation genetic testing, the researchers identified more than 92,000 aneuploid chromosomes and mapped more than three million crossover events, where chromosomes exchange genetic material during meiosis.

Crossovers help ensure that chromosome pairs separate correctly. The researchers found that embryos with fewer crossovers were more likely to be aneuploid, confirming the importance of recombination in maintaining chromosome stability. They also identified common genetic variants associated with both reduced crossover rates and increased risk of maternal meiotic aneuploidy.

One of the key genes found to be associated with an increased risk of aneuploidy was SMC1B, which produces a protein that helps to hold chromosomes together until they are ready to separate. Variation in this and related genes appears to influence how reliably chromosomes segregate during meiosis.

The researchers noted that these findings help explain why aneuploidy risk varies between individuals, beyond the well-established effect of maternal age. While ageing remains a major risk factor, inherited genetic differences may also predispose some women to higher rates of chromosomal error during reproduction.

'Our results demonstrate that inherited differences in these meiotic processes contribute to natural variation in risk of aneuploidy and pregnancy loss between individuals,' Dr McCoy said.

He added that although it will be hard to predict an individual's risk of aneuploidy, these genes are promising targets for future drug development.