Pregnancy loss may occur in as many as 25% of all pregnancies. Most of these losses occur in the first trimester, and about half are caused by genetic or chromosomal issues.
When pregnancy loss occurs three or more times, the losses are referred to as recurrent. Often the cause of recurrent pregnancy loss is difficult to uncover and remains unknown to those experiencing it.
However, two new studies presented at the Association for Molecular Pathology (AMP) 2025 Annual Meeting & Expo, taking place Nov. 11–15 in Boston, provide some answers.
These studies both utilized a cutting-edge technique known as optical genome mapping, which allows researchers to study the structure of genomes at a very high resolution to detect abnormalities often missed by traditional genetic sequencing methods.
Optical genome mapping uncovers hidden causes of pregnancy loss
Researchers at Dartmouth–Hitchcock Medical Center investigated whether OGM could detect harmful chromosomal changes in patients with a family history or risk of recurrent pregnancy loss who had previously undergone traditional genetic testing, such as karyotyping or chromosomal microarray analysis, allowing direct comparison between methods.
On average, researchers found about 40 structural changes in the genome after carefully reviewing the data. The study focused on 238 genes known to be linked to recurrent pregnancy loss (RPL). In two cases, four important RPL-related genes that also play a role in infertility were directly affected by these structural changes. Another case showed a hidden chromosome rearrangement that disrupted other genes not tied to RPL. These results show that optical genome mapping (OGM) can reveal genetic changes that standard tests often miss.
The authors say that, used alongside standard genetic tests, OGM can enhance the diagnostic evaluation of recurrent pregnancy loss, helping clinicians better understand potential genetic causes.
This work was led by Debopriya Chakraborty, Ph.D., a clinical postdoctoral fellow at Dartmouth Hitchcock Medical Center and overseen by Wahab A. Khan, PhD, FACMG and colleagues in the Clinical Genomics and Advanced Technology section at DHMC. Dr. Chakraborty will give a presentation about her findings during a poster session at 9:15 a.m. on Friday, Nov. 14, at the Thomas M. Menino Convention and Exhibition Center in Boston.
Rare chromosome fragile site linked to recurrent pregnancy loss
Some parts of human chromosomes, known as fragile sites, are more prone to developing breaks, gaps or constrictions, especially when DNA is under stress during replication or repair. While fragile sites are known to contribute to genomic instability, their connection to recurrent pregnancy loss is not well studied.
Researchers at Queens University's Kingston Health Sciences Centre and the University of Ottawa investigated the connection between fragile sites and recurrent pregnancy loss. A 33-year-old patient was referred to them after three consecutive early pregnancy losses. Traditional chromosome testing found breaks at the rare fragile site FRA16B in about one-third of her cells. Using optical genome mapping (OGM), they discovered that the repeated DNA segment at FRA16B was unusually large, confirming instability that may be linked to pregnancy loss.
Fragile sites such as FRA16B may be underappreciated contributors to reproductive issues, and incorporating OGM could help identify previously missed causes. Combining traditional cytogenetic testing (such as karyotyping) with OGM provides a clearer, more precise understanding of fragile sites.
This work was overseen by Amira Othman, M.D., Ph.D., PGY-4 diagnostic and molecular pathology resident at Kingston Health Sciences Centre at Queens University, Kingston Ontario, Canada, who will give a presentation about it during a poster session at 9:15 a.m. on Saturday, Nov. 15, at the Thomas M. Menino Convention and Exhibition Center in Boston.
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