It was a medical mystery: When scientists induced a particular genetic mutation in mouse eggs, the resulting embryos would all die in the womb within a week. And yet, people with the same troublesome gene are thriving.

And yet, people with the same troublesome gene are thriving.

«This gene is clearly very deleterious — the mice did not even develop a heartbeat, let alone survive to birth,» said Cecilia Lo, Ph.D., distinguished professor and F. Sargent Cheever Chair of Pitt’s Department of Developmental Biology. «That led us to wonder: How are people who we know have this gene walking around?»

The team found that a protective gene was countering the bad one, explaining why some people with this very deleterious gene not only survived but did so with only an atrial septal defect — a hole in the heart. The findings — reported today in Cell Reports Medicine — provide valuable clinical and personal information to guide families with a history of the disease and could lead to future genetic treatments.

Congenital heart disease is one of the most common birth defects, affecting about 1% of live births. Atrial septal defects — which involve a hole in the wall between the upper chambers of the heart, allowing blood to flow in ways that can damage the heart and lungs — are among the most common forms of congenital heart disease, affecting as many as 10,000 babies born in the U.S. each year.

Working with Brian Feingold, M.D., M.S., medical director of the pediatric heart failure and heart transplant programs at UPMC Children’s Hospital of Pittsburgh, Lo’s team obtained genetic samples from eight members of a family who all had large atrial septal defect. Whole genome sequencing revealed that they all carried an extremely rare mutation in a gene called TPM1 that didn’t appear in more than 900 unrelated samples from people with congenital heart disease; worldwide, it has been seen only twice.

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