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Chromosomal Abnormalities Associated With Recurrent Miscarriage Emerge from Sequencing Study

NEW YORK – Low-pass genome sequencing can help identify chromosomal aberrations in couples suffering multiple miscarriages, a new study has found.

Recurrent miscarriage, or the loss of two or more pregnancies, affects between 1 percent and 2 percent of couples. Chromosomal abnormalities are the major genetic cause of miscarriage and are detected by routine analysis in about 1 in 50 couples.

An international team of researchers performed low-pass genome sequencing on more than 1,000 couples that had experienced multiple miscarriages. As they reported in the American Journal of Human Genetics on Thursday, they were able to detect more than 125 chromosomal abnormalities in total in about 12 percent of couples, boosting detection as compared to routine analysis. This could help identify patients who might benefit from pre-implantation genetic testing and in vitro fertilization.

"It's often difficult to know how to treat or counsel couples when the cause of their infertility remains unknown," co-author Cynthia Morton, director of cytogenetics at Brigham and Women's Hospital, said in a statement. "There are couples who have chromosomal rearrangements that can't be seen by classical methods. The new technique we've used here increases the number of couples who we can see are at risk for having miscarriage."

The researchers sequenced the genomes of 1,090 couples with recurrent miscarriage, or a total 2,180 individuals. Among the 1,077 couples they were able to get results for, the researchers uncovered 127 structural chromosomal abnormalities, in 126 couples, which they validated by PCR and Sanger sequencing. This represents a diagnostic yield of 11.7 percent for low-pass sequencing, the researchers noted.

They further calculated that low-pass sequencing has a sensitivity of about 90 percent, a specificity of 100 percent, a positive predictive value of 99 percent, and is 99 percent accurate.

Balanced translocations were the most common genetic alteration in couples with recurrent miscarriage, affecting nearly 62 percent of couples.

Not all of these abnormalities were captured by the karyotyping the couples initially underwent. Of the 78 couples in which genome sequencing uncovered balanced translocations, 70 were identified via karyotyping, while eight were only detected by sequencing.

However, sequencing missed 10 translocations.

Still, the researchers noted that low-pass sequencing was able to provide a diagnosis for 50 couples that had normal karyotypes.

This suggested to them that low-pass sequencing should be considered as a tool to complement conventional karyotyping. When combined, low-pass sequencing and conventional karyotyping would be able to identify chromosomal abnormalities in 1 in 8 couples with recurrent miscarriage, they estimated.

Being able to identify the source of couples' repeated miscarriages can also aid in treatment. In the study cohort, 26 couples with diagnosed chromosomal abnormalities sought preimplantation genetic testing for aneuploidy and structural rearrangements followed by in vitro fertilization and had a low miscarriage rate of 5 percent.

At the same time, 86 couples with normal sequencing and karyotyping results sought preimplantation genetic testing for aneuploidy followed byIVF and had a miscarriage rate of nearly 33 percent.

Based on this, the researchers calculated that preimplantation genetic testing and IVF among couples with a chromosomal diagnosis leads to an absolute miscarriage risk reduction of 27 percent.