Pre-implantation Genetic Diagnosis (PGD) for VHL

Dr. Wendy Chung

Preimplantation genetic diagnosis (PGD) offers an alternative to more traditional methods of prenatal genetic testing (chorionic villus sampling or amniocentesis) for couples at risk of having a child with VHL. It allows genetic testing to be performed on early embryos prior to implantation and pregnancy. This provides couples with the opportunity to know that any pregnancy they achieve should be unaffected with VHL and avoids the problem of deciding whether to terminate a pregnancy if more traditional prenatal tests such as amniocentesis identify a VHL mutation in the fetus.

Technical advances in molecular genetics now enable us to diagnose VHL from a single cell of an early embryo without harming the embryo. The information gained by PGD is then used to select genetically healthy embryos for placement in the uterus. Other embryos carrying the VHL mutation are discarded or frozen according to the couple’s wishes.

Couples must undergo standard in vitro fertilization (IVF) to use PGD. Healthy, normally developing embryos are biopsied to remove a single cell when the embryo is at the 8 cell stage. The removal of this cell is not felt to affect the health or viability of the embryo or fetus. Genetic testing by molecular genetic techniques using polymerase chain reaction (PCR) are used to genetically diagnose the embryos. The genetic material from the embryos is not altered during a PGD. Unaffected embryos are then implanted in the uterus or cryopreserved (frozen) for future use.

The underlying exact genetic basis (DNA mutation) for your VHL must be known prior to consideration of PGD. Additionally, a laboratory assay must be developed specifically to your mutation and can often take several months to perfect and must be perfected prior to beginning IVF. Few fertility centers in the world have this capability.

I would strongly suggest consultation with a clinical geneticist prior to undertaking this procedure. Genetic counseling is not always routinely included in the IVF process, but it will be important for couples with VHL. I recommend that patients avoid intracytoplasmic sperm injection (ICSI) as part of the IVF since this procedure may be associated with a slightly higher risk of genetic conditions other than VHL and should not be necessary as part of the IVF if the couple has no fertility problems.

The IVF and PGD are not generally covered by health insurance and may cost up to $15,000-$20,000 per cycle depending on your location. It may require multiple rounds of IVF to successfully become pregnant. There may also be risks to a woman with VHL to getting pregnant, so all routine VHL screening should be performed prior to conception and a high risk obstetrician should be consulted to ensure that it is safe to get pregnant.

If you have further questions, please e-mail me at wkc15@columbia.edu.
Wendy K. Chung, M.D., Ph.D.
Herbert Irving Assistant Professor of Pediatrics and Medicine
Director of Clinical Genetics
VHL Clinical Care Center Director at Columbia University

Can any IVF service assist me?
A listing of IVF labs that perform PGD is available at the following websites:

• European Society of Human Reproduction & Embryology (ESHRE), www.eshre.com Scroll down and click on the PGD consortium, a list of worldwide clinics.
• GeneTests, www.genetests.org, a service of the U.S. National Human Genome Institute. Search for preimplantation under the "laboratory directory."
• Internet Health Resources, www.ihr.com. Under Service Providers, click on Preimplantation Genetic Diagnosis

As Dr. Chung describes, however, the actual DNA testing will need to be performed at a special DNA testing facility. Ask whether they are prepared to do single-gene assays, and what their success rate has been. See for example the website of Baylor College of Medicine, www.bcmivf.org/BaylorArt/PreimpGenetic.htm

Is PGD Possible for my Mutation Type?

PGD is currently possible only in cases for which a polymerase chain reaction (PCR) test can be designed. PCR tests can most easily be designed for single base changes or deletions or insertions of one or a small number of bases. Partial or complete deletions of the gene do not lend themselves to PCR based assays.

One family was interested in PGD but the familial mutation was a partial deletion which could not be detected prior to implantation because there was insufficient information on which to base a PCR assay for the deletion.

In cases like this it is sometimes possible to create an assay using an indirect test. It should be noted that this is less accurate than direct testing. There is always some risk that the analysis may be wrong, and in the case of deletions that risk is higher.

Some labs (our own included) are interested in developing a real time-PCR assay to detect deletions in the VHL gene. If we are successful, PGD for families with deletions may be possible in the future.

-- Catherine A. Stolle, Ph.D., Pathology, Children’s Hospital of Philadelphia, Pennsylvania. Dr. Stolle is the world’s leading expert on DNA testing for VHL.

Tissue for Research

Embryonic and fetal tissue is important for research. Please call our Tissue Bank at please call the VHL Tissue Bank at 1-877-221-6374 to arrange transport. See research project described on page 9.