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Advanced Prenatal Genetic Testing: Implications for the Entire Family

Doctor consults with mother to be and husband

“Doctor, this is unbelievable,” the expectant father exclaimed. “You have figured out why everyone in my family has high blood pressure!”

“Well, it’s a little bit more complicated than that,” I explained to him. His wife had just had an invasive prenatal procedure and consented to have a microarray test. Chromosomal microarray technology, on which that test is based, has been used in pediatrics for many years but has only recently been adopted in the prenatal arena. Its implementation in obstetrics has been slow due to the lack of data as well as to the uncertainties and considerations of timing involved in the test.

Traditionally, a woman who undergoes a prenatal invasive diagnostic procedure via amniocentesis (after 16 weeks’ gestational age) or chorionic villus sampling (at 11 to 13 weeks’ gestational age) receives results in the form of a karyotype—23 pairs of banded chromosomes. Cytogeneticists analyze these bands in the lab to determine if there is the correct amount of genetic material. The microarray has been described as a zoomed-in view of the chromosomes. The test looks at the genetic material via a chip and computer analysis and is able to detect much smaller deletions or duplications of DNA—almost like a spell check for DNA. Over the years, many patients have been given results showing normal karyotypes; because of certain abnormalities, the physicians felt there must have been something amiss in the chromosomes, but could not detect anything.

In a study published on December 6, 2012, in the New England Journal of Medicine, for which I was a coinvestigator and coauthor, we explored troubling limits on the accuracy of existing prenatal invasive testing. Among patients whose fetuses had ultrasound abnormalities and who were told the karyotypes were normal, 6 percent had abnormal arrays.

To participate in the array trial, both parents had to provide blood samples to accompany the prenatal sample. Technicians analyzed the blood of the fetus first, and if there was an array abnormality the parents’ blood was analyzed as well. If the abnormality represented a new change in the DNA that was seen only in the fetus, then doctors began to suspect a genetic problem. If, however, this change was seen in the fetus and the same change was also seen in a parent who had no known medical issues, we felt that the change was less likely to cause disease or a major problem. In each case the change in DNA—the missing or duplicated piece—was investigated, and we were able to discuss with the family which if any genes would be affected.

Now, back to our family case: Our expectant father had the same change in his DNA that was seen in the fetus. As geneticists, we were able to research this change on a genome browser and discover which genes could potentially be affected. The genes affected in this case predicted a possible seizure disorder and the potential for hypertension. (There are many genes for both of these medical conditions.) The father thought this was striking because he had a seizure disorder and high blood pressure. His father, uncle, grandfather and great-uncle all had high blood pressure as well. He grabbed my hand and asked me, “What can I do?”

We discussed weight loss, exercise, regular doctors’ visits and being diligent about taking his medications. Clearly, this was a lot more than a postprocedure prenatal genetics consultation for an expectant mom and her unborn child. And this was after we discussed all the implications for the fetus, this pregnancy and future pregnancies.

Most of our array sample results were negative, but some had uncertain results; in those cases we did not know what genes might be affected. Counseling sessions for families with uncertain results were clearly more complicated as they involved the fetus, the parents and extended family members.

I have no doubt that we physicians will see our counseling sessions become a lot longer, and we may need to rely more heavily on our genetics teams. The case discussed above was complicated; the abnormality of the fetus allowed us to discover an abnormality in a parent that was clinically significant. Genetics is a rapidly changing field with many medical and ethical challenges, but I do foresee a time when we will be able to help our patients better control their medical destinies.

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Susan D. Klugman, M.D.

Susan D. Klugman, M.D.

Dr. Klugman is professor of clinical obstetrics & gynecology and women's health, Department of Obstetrics & Gynecology and Women's Health (Reproductive Genetics) at Albert Einstein College of Medicine and Montefiore Health System. As the medical director for Program for Jewish Genetic Health, a collaboration between Einstein and Yeshiva University, she actively speaks to Ashkenazi Jewish women about their heightened susceptibility to being BRCA+.

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