Separate studies led by scientists at Dartmouth Hitchcock Medical Center (DMHC) and Queens University offer some clarity about the hidden causes of recurrent pregnancy loss. Data from both studies is being presented at the annual meeting of the Association for Molecular Pathology (AMP) taking place in Boston, MA from November 11-15.
According to at least one estimate, pregnancy loss may occur in as many as 25 percent of all pregnancies, mostly during the first trimester. About half of the cases are caused by genetic or chromosomal issues. When pregnancy loss occurs three or more times, these are considered recurrent losses. Oftentimes the causes of recurrent pregnancy loss are unclear.
But answers may be coming thanks to new research using optical genome mapping (OGM) technology, a tool for analyzing genome structures at high resolution to detect abnormalities missed by traditional sequencing. In the first study, which was led by Debopriya Chakraborty, PhD, a clinical postdoctoral fellow at DHMC, scientists investigated whether OGM technology could detect harmful chromosomal changes in patients with a family history or at risk of recurrent pregnancy loss. These were also patients who had previously been through traditional genetic tests such as karyotyping or chromosomal microarray analysis, making it possible to compare the method directly.
Chakraborty’s team reported finding 40 structural changes in the genome on average. Furthermore, they looked at 238 genes that were known to be linked to recurrent pregnancy loss (RPL) in the participants. In two cases, they found that important RPL-related genes that also play a role in infertility were directly affected by the structural changes they observed. In another case, they found a hidden chromosome rearrangement that disrupted other genes not tied to RPL.
The second study was led by Amira Othman, MD, PhD, a PGY-4 diagnostic and molecular pathology resident at Queens University in Ontario, Canada. For their analysis, the scientists focused on fragile sites, sections of the human chromosome that are more prone to developing breaks, gaps, or constrictions during DNA replication or repair. These sites are known to contribute to genetic instability; Othman’s team focused on exploring their connection to RPL cases.
Specifically, they looked at data from a 33-year-old patient who had been through three consecutive early pregnancy losses. Prior chromosome testing identified breaks at a rare fragile site dubbed FRA16B in about one-third of her cells. When they analyzed her samples using OGM, they discovered an unusually large repeated DNA segment at FRA16B, which pointed to a possible link between genome instability and pregnancy loss. More broadly, the results suggest that OGM could elucidate a broader role for fragile sites in reproductive issues as well as help with identifying missed cases when used in combination with other cytogenetic testing methods.
