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Repeat Pregnancy Loss Will Be Focus of Genetic Study

July 02, 2021
by Isabella Backman

The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute have awarded a team of Yale researchers a grant for studying recurrent pregnancy loss. The nearly $8 million dollar grant will pave the way for the team to identify genes and types of genetic variation that may be responsible in individuals who experience multiple miscarriages.

“The grant will put Yale on the map as one of the two largest centers in the country for understanding the genetics of pregnancy loss,” says Hugh S. Taylor, MD, chair and Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences and professor of molecular, cellular, and developmental biology.

Fifteen percent of all pregnancies end in miscarriage. Approximately 5% of women will experience two miscarriages, and about 1% of these women will have a third.

“Most women will be pregnant more than once in their lives, and there are so many women who have experienced at least one loss,” says Taylor. “And most of the time, we don’t know why.”

In search for genetic causes, the team will be enrolling individuals who have had multiple pregnancy losses and characterize the genomes of the most recent one. After collecting material from the miscarriage and blood samples from both parents, the researchers will compare the genomes of the three. After excluding cases that can easily be explained by known causes—such as the fetus containing an extra copy of or missing chromosomes—they will take a deeper look at the genome sequencing data and look for other now-invisible mutations.

“Because there haven’t been studies like this that have been done before, we have the ability to find new genes that are essential for development and viability and reveal new biology about what types of mutations affect fertility,” says Ira Hall, PhD, professor of genetics and director of the Yale Center for Genomic Health.

The team hopes to characterize the intolerome—the collection of genes that are essential for human development and life. Currently, only a small minority of the genes necessary for viability is known. This knowledge will help doctors inform prospective parents as they begin reproductive planning.

Most women will be pregnant more than once in their lives, and there are so many women who have experienced at least one loss. And most of the time, we don’t know why.

Hugh S. Taylor, MD

Hall’s lab will be helping to lead the analysis of the genomic data. He only expects a handful out of millions of genetic differences to be important in recurrent pregnancy loss. Part of his role in the study will be to predict which of those millions of variants may be responsible.

Fifteen years ago, this project would have been unaffordable. Since then, however, there have been huge advances in genome sequencing technologies that allow scientists to do genome sequencing in large numbers of people in a fast and affordable way. Now, during a time where human genomes are being sequenced for a wide variety of projects, the Yale team has a solid foundation of knowledge of genetic and human variation that allows it to put its observations from this project in context.

Yale already offers an ongoing recurrent pregnancy loss program to help treat and offer support to those struggling with multiple miscarriages. The new study will provide specialists with valuable insight for understanding and addressing cases that are now unexplained.

“Miscarriages can be just devastating and heartbreaking, especially when they’re repetitive,” says Taylor. “We will be one of the leading centers in the country and our patients will have the first access to this groundbreaking technology that will start to understand why women can lose a pregnancy.”

In addition to Taylor and Hall, Yong-Hui Jiang, MD, PhD, and Uma Reddy, MD, MPH, will be significant contributors to the study. Jiang is professor of genetics and chief of medical genetics. Reddy is professor of obstetrics, gynecology, and reproductive sciences, and section chief of maternal-fetal medicine

Submitted by Robert Forman on July 02, 2021