Raul Piña-Aguilar

Cynthia Morton

When a couple loses a pregnancy, and especially when the same couple loses multiple pregnancies, doctors are often at a loss to explain why. For about 40 to 60 percent of couples who experience recurrent miscarriages, the condition remains unexplained, even after costly testing.

Chromosomal abnormalities — rearrangements of large chunks of DNA — in the genomes of one or both individuals trying to conceive are thought to be one of the major genetic causes of recurrent miscarriages, which is defined as having two or more pregnancy losses. Routine chromosome analysis can currently detect these abnormalities in about one in 50 couples. A new study by investigators from the Brigham, Shandong University and The Chinese University of Hong Kong describes a special genetic-sequencing technique, known as low-pass genome sequencing (GS), that can reveal chromosomal abnormalities in more couples than traditional testing — increasing detection to one in nine couples. The findings are published in The American Journal of Human Genetics.

“Recurrent miscarriages carry an underappreciated psychological and financial burden for affected couples. It’s often difficult to know how to treat or counsel couples when the cause of their infertility remains unknown,” said co-author Cynthia Morton, PhD, director of Cytogenetics at the Brigham. “There are couples who have chromosomal rearrangements that can’t be seen by classical methods. The technique we’ve used here increases the number of couples who we can detect who are at risk for having a miscarriage.”

Building on a previous collaboration, researchers from the Brigham worked with colleagues at The Chinese University of Hong Kong and Shandong University to analyze samples from nearly 1,100 couples who had two or more pregnancy losses. Couples were enrolled from recurrent miscarriage clinics at Hong Kong and Shandong universities. Upon performing both traditional chromosome analysis and low-pass GS on the samples, the team detected 127 chromosomal abnormalities using low-pass GS, accounting for approximately 12 percent of the couples. By comparison, traditional chromosomal analysis detected 86 chromosomal abnormalities.

“This a perfect example of the fundamental role that genetics can serve to help patients with infertility,” said co-author Raul E. Piña-Aguilar, MD, a postdoctoral fellow in the Morton lab.

“We have found that additional couples with recurrent miscarriages have chromosomal rearrangements. Undoubtedly, these couples are the ones who will benefit most from personalized intervention.”

A technique known as pre-implantation genetic testing can help couples with genetic abnormalities conceive through in vitro fertilization. Such approaches are expensive and, until now, it’s been unclear which patients with recurrent miscarriages would benefit most from genetic testing of their embryos.

“Our results suggest that applying low-pass GS could help identify a larger subgroup of patients at increased risk of subsequent miscarriages who might take advantage of pre-implantation genetic testing,” Morton said.

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