A Scientific First: Preimplantation Genetic Testing for Infertile Couple Frees Baby of Disfiguring Heart Ailment

Feb 2, 2004

New York, NY

With the help of NewYork-Presbyterian/Weill Cornell scientists, a couple now have a healthy baby boy, free of a disfiguring genetic ailment that has plagued the father and his family for generations.

Craig Basson, M.D., Ph.D., Jie He, M.D., Deborah McDermott, C.G.C., and colleagues used a technique known as preimplantation genetic diagnosis (PGD) to help the couple's baby steer clear of a rare condition called Holt-Oram syndrome, according to a report in the American Journal of Medical Genetics.

We were delighted that we were able to help this family. It is extremely exciting to see the fruits of years of research actually be able to help our patients, said senior investigator Dr. Basson, Director of Cardiovascular Research in the Greenberg Division of Cardiology at the Weill Medical College of Cornell University and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

While at least 500 healthy children have been born worldwide after preimplantation genetic diagnosis for other disorders, the boy was the first to be born free of Holt-Oram syndrome, a condition that causes birth defects affecting the heart and limbs. It is the most common heart-hand syndrome, occurring about 1 in 100,000 live births.

The effects of the inherited condition can be severe or relatively mild. While the 30-year-old father had some arm and hand abnormalities, including a missing thumb, his heart function was relatively good. However, he has a niece that died in childhood after heart surgery and a nephew with severe heart problems.

We have worked with his family for about a decade, and their contributions to even our earliest research on Holt-Oram syndrome have been invaluable. It is very gratifying for our research to be able to help them, said Dr. Basson, who is also Associate Professor of Medicine and Associate Professor of Cell and Developmental Biology at Weill Cornell Medical College.

When the man and his 42-year-old wife found they were struggling with infertility, they came to NewYork-Presbyterian/Weill Cornell's Center for Reproductive Medicine and Infertility for help. The Center is a leader in preimplantation genetic diagnosis, or embryo biopsy, using the technique to help prevent hemophilia, sickle-cell anemia, Down's syndrome, Tay-Sachs disease, and, most recently, retinoblastoma (eye cancer), among other conditions.

After undergoing extensive genetic counseling and testing, the couple discovered the man's sperm count was normal, but his wife had diminished ovarian reserve, a very low level of egg production that was contributing to infertility.

While Holt-Oram syndrome does not cause fertility problems, people with the condition have a 50 percent chance of passing the disease on to their offspring.

The couple decided to undergo in vitro fertilization (IVF), using donor eggs from NewYork-Presbyterian/Weill Cornell's Center for Reproductive Medicine and Infertility Oocyte Donation Program. As a research study in association with the IVF technique, in which egg and sperm are mixed in the laboratory, the doctors tested the embryos for the gene mutation that causes Holt-Oram syndrome. The mutation is in a gene called TBX5, a so-called transcription factor because it helps regulate other genes.

The scientists hoped to exclude those embryos that contained the gene mutation, and transfer only healthy embryos to the woman's uterus. They conducted the test by taking a single cell from the developing embryos, which contain 6-8 cells at this stage, and amplifying the DNA to test for the gene mutation.

While the general protocol used is standard for preimplantation genetic diagnosis (worked out in major part by our collaborators such as Isaac Kligman, M.D., in Weill Cornell's IVF Program), every mutation requires a specifically custom-designed test. We devoted considerable effort to tailoring a sensitive test to this specific TBX5 mutation, said Dr. Basson.

In addition to Dr. Kligman, other NewYork-Presbyterian/Weill Cornell co-authors included Drs. Yan Song and Fred Gilbert.

The researchers found that four of the five embryos resulting from IVF were healthy and free of the damaging mutation. Thirty-eight weeks after two of the embryos were transferred into the woman's uterus, she had a healthy baby boy.

Our demonstration that preimplantation genetic diagnosis is feasible for Holt-Oram syndrome also implies that PGD is an option for couples with normal fertility, the researchers report in the journal.

However, couples should be counseled that the technique is not a 100 percent guarantee of a healthy baby. Studies of preimplantation genetic diagnosis for other conditions have suggested that the technique is not foolproof because of uncertainties in gene testing.

We continue to consider new advances in providing diagnosis and therapy for our patients. It is our hope that understanding the mechanism of TBX5 action may ultimately provide specific therapy for Holt-Oram syndrome. However, preimplantation genetic diagnosis provides a way to treat the family, since children who are unaffected will not have affected children, and thus PGD provides a mechanism to eliminate Holt-Oram syndrome from the family, said Dr. Basson.

The study was funded by the Michael Wolk Heart Foundation and the Cornell Vascular Medicine Foundation.