Master Class

Preimplantation Genetic Diagnosis and Screening


It was my job to explain to the baby's parents what the disorder was and how it happened. Many of the babies I saw had an autosomal recessive disorder, and it was necessary to explain to the baby's mother and father how this awful disease suddenly appeared in their child, and tell them that they faced a 25% risk of its happening again should they decide to have more children. Their options for the future, I would tell them, would be to adopt, to elect not have any more children, to use an anonymous donor for eggs or sperm, or—as many couples do—to carefully roll the genetic dice again with hopes of a better outcome.

In the last scenario, I would explain, the parents would have the opportunity to have a chorionic villus sampling or amniocentesis. But it goes without saying that the 12–15 weeks that unfold before such testing is done are often filled with anxiety: first, about having the test, and second, about the decision to be made if the results are not favorable.

Today, obstetricians have good reason to present such parents with another option—preimplantation genetic diagnosis (PGD)–and to be aware of its capabilities and limitations. Developments in PGD mean that we, also, in all of our preconceptual obstetrical work, have good reason to be cognizant of ethnicity-based risks for genetic disorders and to advise patients, when indicated, to have genetic screening themselves.

We can use PGD today, in conjunction with in vitro fertilization, to test for over 250 serious diseases and conditions caused by mutations or chromosomal abnormalities. Parents who choose the technology—usually couples who know they carry mutations or who have had another baby or a family member with a serious inherited illness—can learn that an embryo is free of the disease that their family is prone to, and can thus start a pregnancy with a commitment to continuing it.

The Genetics, the Process

As obstetricians, we are not trained geneticists. Therefore, it is helpful for us and for our patients if we understand the basic genetics behind PGD, and appreciate how PGD pushes diagnostic technology to its absolute limits—both its theoretical limits and its practical limits.

Every cell taken from an embryo (or any cell in our body) contains all the genes needed to make a new, complete individual. Each cell's DNA contains just four letters of the genetic alphabet: A, T, G, and C. The way in which these letters are strung together, just as letters are put together to make a book, will tell that cell what to do.

We can think of chromosomes as books of the gigantic encyclopedia of life, and genes as paragraphs within these chromosome books. Each chromosome has thousands of genes, most of which contribute something unique to the story of who we are, just as most paragraphs in a novel or encyclopedia contribute a unique element to the story or knowledge base. Some genes do not appear to be as important to our health as others, just as some paragraphs seem like “filler” in a story.

All genes have a defined beginning and a defined end, and just as a paragraph has an indentation, a gene has a promoter. Genes are made up of little bits called exons, just as paragraphs are made up of sentences. Some genes are gigantic; the gene whose mutation causes muscular dystrophy, for instance, would be equivalent to a paragraph about 158 pages long. Other genes are tiny, similar to a short phrase.

We all carry hundreds and hundreds of typographical errors in our personal encyclopedia, some of them inactivating the gene paragraph that contains them. Fortunately, the errors we inherit from our mothers are generally not matched by the errors we inherit from our fathers. Every once in a while, though, we choose a mate with a gene mutation in the same paragraph. When this occurs, the baby does not have a “backup” copy of the intact gene paragraph, and a recessive disease can occur.

Such unfortunate pairings happen more often in couples of similar ethnicity because many gene mutations are ancestral in a given ethnic population. Thus, one of our roles in preconceptual counseling is to think about the possibility that a patient who wants to discontinue birth control and start a family might carry a gene mutation for an inherited disorder common to his or her ethnic background.

In couples of Northern European ancestry, we think first of cystic fibrosis (with a carrier frequency of about 1 in 29 in the United States) and spinal muscular atrophy (1 in 5). In African Americans, we worry about sickle cell anemia (1 in 22).

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