Risk Factors for Seven Common Aneuploidies: Successes, Limitations, Missed and New Opportunities

Advanced maternal age is a risk factor for common autosomal trisomies, 47,XXY and 47,XXX, and rate schedules by age have been used in genetic counselling and screening protocol design. However, if there is a family history of an affected offspring, rates require adjustment, about which there are considerable uncertainties. These depend upon likely important additional factors, both genetic (e.g., cryptic parental mosaicism) and environmental, some independent of age whilst other age associated. The observed high recurrence risk of some aneuploidies, as well as heterotrisomic recurrence may result from currently unidentified hereditary predisposing factors. Pregnancy losses are not routinely karyotyped, and as most aneuploidies are non‐viable, this has diminished awareness of such a possible etiological contribution in this group. Aneuploidy screening has led to early diagnosis of most affected pregnancies but has complicated the research process. The advent of cell‐free DNA screening, which is simpler and maximal, could be an opportunity to refocus on understanding aetiology through epidemiology. We advocate cooperation between large population‐based screening programs, revitalised birth defect registers, variant databases, and electronic medical record systems. There is a need to reap the benefits of advanced genomic technologies and combine them with traditional epidemiology to further understand aneuploidy origins.