Detecting Genetic Disorders in the Unborn

Pam Harrison

April 03, 2013

It is now possible to sequence the entire genome of an unborn baby with only a sample of the mother's blood, California researchers report. This means that metabolic and immunologic disorders can be detected prior to delivery and treatment can be started immediately after birth.

"What happens now is that infants suffer as symptoms become apparent after birth because it takes time to determine the diagnosis," said Stephen Quake, DPhil, professor of bioengineering and applied physics at Stanford University in California.

"There is value in knowing before infants are born that they have a treatable disorder. Then they can be treated immediately after delivery without a lot of confusion early on," he explained.

At the Future of Genomics Medicine VI meeting in La Jolla, California, Dr. Quake pointed out that a proportion of cell-free DNA in a pregnant woman comes from the fetus.

Dr. Quake and his team from Stanford University used this fact to develop a diagnostic test to noninvasively identify Down's syndrome and other aneuploidies, which are disorders arising from an abnormal number of chromosomes (Nature. 2012;19:487:320-324). The test is now used in prenatal clinics.

To measure the entire fetal genome noninvasively, Dr. Quake's team applied the same chromosome-counting principle to fetal genome analysis that they developed for aneuploidy detection. The principle allows researchers to count chromosomes, haplotypes, and even individual alleles in maternal plasma DNA.

Because the fetal genome is a combination of the 4 parental chromosomes, 3 of these haplotypes exist in maternal plasma for each region of the genome: the maternal haplotype that is transmitted to the fetus, the maternal haplotype that is not transmitted to the fetus, and the paternal haplotype that is transmitted to the fetus.

There is value in knowing before infants are born that they have a treatable disorder.

As the Stanford researchers show in Nature, within each pair of parental haplotypes, the transmitted haplotype is overrepresented, relative to the untransmitted one. "By...counting the number of alleles specific to each parental haplotype, one can deduce the inheritance of each parental haplotype and hence build the full inherited fetal genome," they explain.

The researchers tested this method of molecular counting in 2 pregnant women, 1 of whom had DiGeorge syndrome.

Whole-genome and exome sequencing showed that the infant whose mother had DiGeorge syndrome inherited the disorder. DiGeorge syndrome is caused by a short deletion of chromosome 22, which leads to cardiac, neuromuscular, and cognitive symptoms.

"Some pregnant women are tested with amniocentesis," Dr. Quake told Medscape Medical News. However, that involves a small risk for pregnancy loss. This puts people in a quandary: Do they risk the pregnancy for the sake of potentially unimportant genetic information, or do they wait and see what happens after birth?

"The molecular counting methods offer a gateway to comprehensive noninvasive prenatal diagnosis of genetic disease," the researchers write. "We anticipate that there is no technical barrier and many practical applications to having the entire fetal genome determined noninvasively in clinical settings," they add.

Noninvasive Prenatal Diagnosis

In an editorial on fetal genes in mother's blood also published in Nature (2012;487:304-305), Diana Bianchi, MD, executive director of the Mother Infant Research Institute at Tufts Medical Center in Boston, Massachusetts, points out that the Stanford team has shown that a fetal diagnosis can be made noninvasively even when the fetus shares the same mutation as the mother — something that has proven highly elusive until now.

Still, she notes, identifying mutations in the unborn raises ethical and practical questions about how prospective parents and physicians use this information. What if, she posits, parents discover that a fetus is carrying a mutation that will give rise to Parkinson's disease at a much later stage of life?

"Will expectant couples want to know this sort of information?" Dr. Bianchi asks. What if the fetus harbors not just a single point mutation, but many other mutations that could give rise to multiple disorders later in life? She wonders what kind of resources will be needed to provide parents with counseling on the implications of genetic data.

"Before the vast amounts of information acquired from fetal-genome sequencing can be applied in a useful manner, the gap between technology and clinical interpretation must be narrowed," Dr. Bianchi advises. In addition, "substantial investment is needed [to teach] healthcare providers about the human genome."

Dr. Quake and Dr. Bianchi report having a financial interest in Verinata Health, which offers a genetic test for Down's syndrome and other chromosomal abnormalities.

Future of Genomic Medicine VI. Presented March 7, 2013.