Observational study finds maternal gene variants linked to aneuploidy risk — Evidence Review
Published in Nature, by researchers from Johns Hopkins University
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Table of Contents
A large-scale study has identified specific maternal gene variants associated with an increased risk of chromosomal abnormalities in embryos, shedding light on genetic factors contributing to pregnancy loss. Existing research generally supports a genetic role in miscarriage risk, and the new findings from Nature align with and expand upon previous work by pinpointing maternal variants linked to aneuploidy.
- Multiple studies have previously reported that both common and rare maternal genetic variants may contribute to pregnancy loss, with mechanisms involving chromosomal segregation errors, immune factors, and placental biology 1 4 11 12.
- The new study specifically implicates gene variants affecting crossover recombination during egg formation, a process already known to be error-prone with advancing maternal age and associated with aneuploidy risk 10 13.
- While earlier research documented associations between pregnancy loss and polymorphisms in immune, coagulation, or metabolic genes, the present findings offer genome-wide evidence for meiosis-specific maternal variants, helping to clarify underlying biological pathways 1 4 12.
Study Overview and Key Findings
Pregnancy loss remains a significant public health concern, with about half of first-trimester miscarriages attributed to chromosomal abnormalities. However, the genetic risk factors in mothers, particularly those underlying chromosomal segregation errors (aneuploidy) in eggs, have remained poorly characterized. This new study, leveraging data from more than 22,000 women undergoing IVF, represents a major advance by systematically analyzing maternal genetic variants that may predispose to aneuploid embryos—a key cause of miscarriage and reduced fertility, especially with advanced maternal age.
| Property | Value |
|---|---|
| Study Year | 2026 |
| Organization | Johns Hopkins University |
| Journal Name | Nature |
| Authors | Carioscia, S. A., Biddanda, A., Starostik, M. R., Tang, X., Hoffmann, E. R., Demko, Z. P., McCoy, R. C. |
| Population | Mothers undergoing in vitro fertilization |
| Sample Size | n=22,850 |
| Methods | Observational Study |
| Outcome | Genetic variants linked to aneuploid embryos |
| Results | Identified gene variants linked to aneuploidy risk in mothers. |
The study used genome-wide association analyses of maternal DNA and detailed embryo genetic testing to identify maternal gene variants associated with higher rates of embryonic aneuploidy. The strongest associations were found with variants in SMC1B and C14orf39—genes involved in chromosome cohesion and crossover recombination, both crucial for proper chromosomal separation during egg formation. The study also demonstrated that women with specific variants in these genes had lower crossover counts and higher risk of producing embryos with chromosomal imbalances, linking genetic predisposition to the biological process underlying aneuploidy.
Literature Review: Related Studies
To place these findings in context, we searched the Consensus database of over 200 million research papers using the following queries:
- maternal gene variants pregnancy loss
- aneuploidy risk maternal genetics
- genetic factors miscarriage outcomes
The following table summarizes key themes and findings from the literature:
| Topic | Key Findings |
|---|---|
| What maternal genetic factors influence pregnancy loss and aneuploidy risk? | - Both common and rare maternal gene variants—including those in meiosis, immune, and adhesion pathway genes—are associated with increased risk of miscarriage and aneuploidy 1 2 4 12 13. - Maternal age-related changes in chromosome cohesion and recombination are major contributors to oocyte aneuploidy 10. |
| How are mechanisms such as recombination errors and immune factors implicated in miscarriage? | - Recombination failure, impaired chromosome cohesion, and immune dysregulation (e.g., HLA gene variants) have all been linked to increased risk of pregnancy loss 4 10 12 14. - Errors in crossover recombination during meiosis are a well-established cause of aneuploidy 10. |
| What is the utility of genetic screening and diagnostics in identifying at-risk pregnancies? | - Noninvasive prenatal testing and preimplantation genetic diagnosis can accurately detect fetal chromosomal abnormalities, potentially aiding in risk stratification 6 7 8 9. - Sequencing approaches (whole-exome, whole-genome) are identifying novel variants for use in diagnostic panels 1 2 5. |
| What are the broader impacts of maternal genetics on pregnancy outcomes? | - Genetic factors contribute not only to miscarriage but also to risks of gestational diabetes, preeclampsia, and adverse outcomes, with multi-locus effects often observed 3 11 12. - Large-scale studies are revealing the complex genetic architecture of miscarriage and related complications 3 11. |
What maternal genetic factors influence pregnancy loss and aneuploidy risk?
Recent research has increasingly focused on the genetic contributions to pregnancy loss, moving beyond chromosomal abnormalities in embryos to consider maternal variants that may predispose to such errors or other complications. The new study's identification of meiosis gene variants aligns with prior findings that both common and rare maternal genetic variants, including those involved in meiosis, immune function, and cell adhesion, can increase miscarriage risk 1 2 4 12 13.
- Prior systematic reviews and sequencing studies have identified a wide range of maternal gene variants linked to recurrent miscarriage, including both monogenic and polygenic contributions 1 2 4 12.
- Maternal age is a well-established risk factor for aneuploidy, in part due to age-related deterioration in chromosome cohesion and recombination machinery 10.
- The new study's focus on crossover recombination genes adds a novel layer, directly connecting maternal genotype to the biological process of aneuploidy formation 10.
- Some maternal genetic factors may have population-specific effects, as seen with immune-related variants in certain ancestries 4.
How are mechanisms such as recombination errors and immune factors implicated in miscarriage?
A growing body of literature supports the role of both mechanical (e.g., recombination errors) and immunological (e.g., HLA polymorphisms) mechanisms in pregnancy loss. The current study's emphasis on crossover recombination errors is supported by prior analyses showing these are principal contributors to aneuploidy, especially with increasing maternal age 10 14.
- Recombination failure and reduced crossover events increase the likelihood of improper chromosome segregation, leading to aneuploid embryos and subsequent pregnancy loss 10.
- Variants in immune function genes, such as HLA, also confer risk, highlighting the multifactorial nature of miscarriage etiology 4 12 14.
- The present research ties genetic variation in recombination machinery to both the probability of crossover and risk of aneuploidy, suggesting a shared genetic pathway 10.
- Other studies underscore the need to consider both immune and non-immune mechanisms in understanding recurrent miscarriage 12 14.
What is the utility of genetic screening and diagnostics in identifying at-risk pregnancies?
Advances in genetic testing—including noninvasive prenatal screening and preimplantation genetic diagnosis—have improved the ability to detect chromosomal abnormalities and stratify risk in pregnancies, especially for women undergoing fertility treatment 6 7 8 9. The identification of risk-associated maternal variants in the new study could inform future diagnostic approaches.
- SNP-based and massively parallel sequencing tests are effective in detecting fetal aneuploidy, even in low-risk populations, though confirmatory testing remains important 6 7 8.
- Whole-exome and whole-genome sequencing are uncovering novel gene variants that could be incorporated into diagnostic panels for women with recurrent pregnancy loss 1 2 5.
- Knowledge of specific maternal risk variants may, in the future, enable more personalized risk assessment and targeted counseling 1 5.
- Current clinical application of maternal genotype information is limited, as individual variants explain only a small fraction of overall risk 1 7.
What are the broader impacts of maternal genetics on pregnancy outcomes?
Beyond miscarriage, maternal genetics exert influence over a range of pregnancy outcomes, including gestational diabetes, preeclampsia, and preterm birth. The complex, multi-locus nature of these effects is being clarified by large-scale genome-wide studies 3 11.
- Genome-wide association studies are identifying multiple loci associated with miscarriage, gestational age, and adverse outcomes, many of which overlap across conditions 3 11.
- Some genetic variants affect biological processes relevant to placental development, immune tolerance, or metabolic pathways 3 11 12.
- The complex interplay between maternal, paternal, and fetal genetics is increasingly recognized as important for understanding pregnancy complications 11.
- Large biobank and multi-ancestry studies are critical for uncovering the full genetic architecture underlying pregnancy outcomes 3 11.
Future Research Questions
While this study represents a significant advance in understanding the genetic underpinnings of pregnancy loss, many questions remain. Future research is needed to clarify the functional impacts of identified variants, explore gene-environment and gene-age interactions, and assess the potential for translating genetic findings into clinical practice.
| Research Question | Relevance |
|---|---|
| How do specific maternal meiosis gene variants mechanistically lead to aneuploidy in human oocytes? | Understanding the functional consequences of these variants could reveal new targets for intervention and clarify the precise biological pathways involved in chromosomal segregation errors 10. |
| Can maternal genetic risk scores be developed to predict aneuploidy and pregnancy loss risk? | Polygenic risk models could enable personalized reproductive counseling if validated in diverse populations, but current individual variant effects are small 1 4 7. |
| What is the role of gene-environment interactions in modulating the impact of maternal variants on pregnancy outcomes? | Environmental and lifestyle factors may interact with genetic predispositions, influencing the risk of aneuploidy and miscarriage, especially as women delay childbearing 10 13. |
| How do maternal immunogenetic variants and meiosis-related variants interact to affect pregnancy loss risk? | Both immune and chromosomal segregation pathways contribute to miscarriage risk; their combined or interactive effects need clarification to develop comprehensive risk models 4 12 14. |
| Can therapeutic interventions target meiosis or chromosome cohesion to reduce aneuploidy in older women? | There is evidence that exogenous factors may mitigate age-related aneuploidy; exploring targeted therapies could improve fertility outcomes in advanced maternal age 10. |
This article was prepared to provide an evidence-based overview of recent advances in the genetics of pregnancy loss, integrating new findings with the broader scientific literature.