Preimplantation genetic diagnosis: Which patients to test and other controversies

Preimplantation genetic diagnosis (PGD) is a major advance, one that has given us the ability to diagnose a genetic disorder before implantation at 6 days postconception. For more than a decade, it's been an important addition to prenatal genetic diagnosis.^1,2 Assisted reproductive technology (ART) is required, most commonly in vitro fertilization (IVF), followed by removing and analyzing a single blastomere at the eight-cell stage (3 days). Embryos subsequently classified as unaffected by genetic defects are transferred, and affected embryos are not. Analysis of polar bodies can usually accomplish the same goal. Because ART is required and the process is expensive and stressful, some indications are controversial, and guidelines are not always consistent or followed.^3,4 My goal here is to explain the current indications for PGD, addressing these controversies.

Avoiding clinical termination of affected pregnancies

Of all the couples in the United States undergoing traditional prenatal genetic diagnosis, only half are prepared to terminate a pregnancy if their fetus is deemed abnormal. So on the one hand, many couples wish to be reassured that their fetus is normal, but on the other, they are not prepared to terminate an affected clinical pregnancy. Only PGD allows these couples the option of avoiding an abnormal child. PGD to avoid clinical termination has been a common attraction since the procedure was introduced in the 1990s; almost half of European couples undergoing PGD cite this as a reason.⁵ Even couples who have no religious objections to termination find traditional prenatal diagnosis daunting when termination becomes necessary in more than one pregnancy. In couples at risk for autosomal recessive disorders (e.g., cystic fibrosis), it's not rare to have consecutive fetuses affected (1/4 × 1/4 = 1/16).

When pregnancy involves a prospective parent at risk for an adult-onset autosomal dominant disorder, PGD is the only pragmatic approach. This at-risk parent may be clinically normal but have a mutant gene not yet clinically manifested. Typically, the parent's at-risk status came to light because one of the prospective parents has a mother or father with such a disorder. If a patient's parent has the autosomal dominant disorder Huntington disease, for example, the risk for any given fetus is 1 in 4 (1 in 2 that the prospective parent is affected times 1 in 2 that, if so affected, the mutant gene will be transmitted).

The at-risk parent may not wish to learn of his/her genotype, but may still want to avoid transmitting the mutant gene to the couple's offspring. Through PGD, the at-risk adult can do so, remaining unaware of his or her own status. The strategy requires screening all embryos, transferring only those unaffected, and never disclosing information on any individual embryo. The scenario must be repeated in subsequent cycles, even if tests reveal the at-risk parent to be unaffected. Otherwise, at-risk patients would readily deduce their genotype.

Transfer of HLA-compatible embryos

Another unique capability of PGD involves identifying HLA-compatible embryos for transfer. Suppose a couple desiring a pregnancy has had a child with a lethal autosomal recessive disorder characterized by bone marrow failure. If stem cell transplantation could repopulate the child's bone marrow with genetically normal precursors, the affected sibling would be able to survive. Stem cell transplantation is highly successful if HLA-compatibility exists between donor and recipient, but considerably less successful when it does not.

A sibling is the most likely source for HLA-compatible stem cells-including cells from a newborn sibling's umbilical cord blood. Although amniocentesis or chorionic villus sampling can identify HLA- compatible fetuses, only 1 of 4 fetuses are HLA compatible. The prospective fetuses will usually also be at risk for the autosomal recessive disorder causing the sibling's bone marrow failure; but 3 of 4 fetuses would be normal. What's more, the overall likelihood of a genetically normal HLA-compatible fetus is only 3 in 16 (i.e., a 1 in 4 likelihood of HLA-compatibility multiplied by a 3 in 4 likelihood of being unaffected). Only PGD provides a practical method for yielding an unaffected and HLA-compatible embryo. The most common indications are β-thalassemia, Fanconi anemia, Wiskott-Alderich syndrome, and acute leukemia.⁶ Aneuploidy can be determined on the same embryos.⁷