Chromosomal Abnormalities Common in Couples With Recurrent Miscarriage

By Will Boggs MD

November 09, 2019

NEW YORK (Reuters Health) - Almost 12% of couples with recurrent miscarriage have chromosomal abnormalities, according to results of low-pass genome sequencing (GS) studies.

"Although it is commonly recognized by clinicians that individuals with balanced chromosomal abnormalities can produce abnormal pregnancies that may end in a miscarriage more frequently, our findings reveal with GS that it is surprisingly more frequent than previously thought, and expands the subgroup that is at higher risk for miscarriage," Dr. Elvis Zirui Dong of Shandong University, in Jinan, China, and the Chinese University of Hong Kong, told Reuters Health by email.

Several recent studies have demonstrated that GS can delineate breakpoints of balanced translocations/inversions and detect additional copy-number variations (CNVs) compared with chromosomal microarray analysis.

Based on GS results, Dr. Dong and colleagues identified 127 balanced structural chromosomal abnormalities in 11.7% of 1,077 couples with recurrent miscarriages, including 78 subjects with balanced translocations and 48 with inversions.

This prevalence represents a 16.7-fold increase compared to the rate of 0.7% in participants in the 1000 Genomes Project who were not known to have chromosomal rearrangements and presumed to represent a normal control population, the researchers note in their report, online October 31 in The American Journal of Human Genetics.

GS also identified 2,124 copy-number losses and 4,623 gains, representing two deletions and 4.2 duplications per couple.

The researchers note that "the extent of the contribution of the detected CNVs to recurrent miscarriage remains to be established, but our data provide further evidence of the increased detection and precision of GS."

Ten of 50 couples with additional diagnoses by low-pass GS but with normal karyotypes subsequently had a spontaneous conception, and five of these couples reported miscarriage or fetal structural abnormalities.

Based on outcomes of 26 couples with an abnormal chromosomal diagnosis who sought in vitro fertilization and preimplantation genetic testing (69.2% clinical pregnancy rate, resulting in 18 live births and only one miscarriage), the authors suggest that such intervention can result in a significantly lower miscarriage rate.

"Clinical guidelines around the world are inconsistent in the recommendation about chromosomal testing for recurrent miscarriage couples," Dr. Dong said. "Our paper substantiates the fundamental role of such testing and supports a personalized intervention in about 12% of couples."

"Cytogenetics (the study of chromosomes) is a dynamic discipline that is moving to a more DNA-sequencing-based test which provides better diagnosis and greater precision," he added. "This precision will empower diagnoses not only for recurrent-miscarriage couples but also for understanding the biological basis of other diseases in women's health."

The study had no commercial funding. Several of Dr. Dong's coauthors are employed by companies providing genomics.


Am J Human Genetics 2019.