Would you want to know if your unborn baby is at risk of autism?
Researchers wrapping up a 4,406-patient study say that a new genetic test that analyzes fetal DNA in more detail than current prenatal tests, can detect additional abnormalities, including those associated with autism and other intellectual disabilities, making them a potentially more accurate way of predicting disease risk.
Chromosomal microarray analysis, which compares specific regions of an unborn baby’s DNA to that of a normal genome, should be offered to all expectant mothers, say researchers at Columbia University who led the study. The current method of prenatal testing for genetic diseases, known as karyotyping, involves a cruder analysis of DNA as it is packaged in chromosomes in fetal cells. Karyotyping can identify broad abnormalities such as changes in the number of chromosomes or structural aberrations; it is used to diagnose conditions such as Down syndrome, for example, which results from an extra chromosome. Microarray testing, which uses the same invasive methods as karyotyping — by sampling the chorionic villus cells from the placenta, or amniocentesis, which extracts cells and fetal DNA from amniotic fluid—can do that and more, says Dr. Ronald Wapner, director of reproductive genetics at Columbia University Medical Center and lead author of the study published in the New England Journal of Medicine.
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“Karyotyping has been the gold standard for 60 years,” he says. “Microarray identifies everything a karyotype identifies and more, so why wouldn’t people want more information?”
All of the women from the 29 centers nationwide participating in the study had a reason for needing prenatal diagnosis, ranging from their advanced age (over age 35) to an abnormal result for Down syndrome screening, or aberrations on ultrasound. Microarray was able to uncover chromosomal deletions or duplications—places where there were extra or missing pieces of DNA—in 6% of cases where ultrasound had found a suspected problem but a karyotype revealed nothing was wrong. In women over 35 or those with positive Down syndrome screening results, microarray found an abnormality in one out of every 60 pregnancies where karyotyping had turned up nothing. Even in instances where women had normal ultrasounds and normal karyotypes, microarray identified genetic changes known as copy number variations (CNV), or an abnormal amount of DNA in certain regions of the genome, in 1.7% of cases. “Microarray is like spellcheck for fetal DNA,” says Dr. Susan Klugman, director of reproductive genetics at Montefiore Medical Center in the Bronx, which served as one of the study’s main recruiting sites. “If there is an error, it comes up.”
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Because it involves a deeper analysis of a developing baby’s DNA, microarray analysis can also find numerous diseases that are not household names, including DiGeorge syndrome, which stems from a defect in chromosome 22 and is associated with heart abnormalities and a 25% risk of becoming schizophrenic later in life. “There are a lot of very serious conditions that can’t be seen by karyotyping,” says Wapner.
The problem with microarray testing, however, is that it may provide too much information. Exactly how relevant the copy number variations are for disease remains less certain. CNVs have been linked to autism, for example, but that doesn’t mean that the presence of these changes makes autism inevitable, nor does it provide clues to how severely the child may be affected by the developmental disorder. And for some CNVs, it’s not known whether they have any clinical significant at all, raising sticky ethical issues for expectant parents who provided the additional microarray information and are faced with deciding for which disorders terminating a pregnancy would be worthwhile. “When encountered in the prenatal setting, this increased range of phenotypic features can make genetic counseling challenging,” write the authors. “Many of these copy-number variants do not always result in severe impairments.”
Then there is the price tag for microarray analysis, which ranges from $1,200 to $1,500, while karyotyping costs $600.
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Still the analysis shows that unclear genetic findings occur in about 1% of karyotypes, so such uncertainty is not unique to microarray analysis or genome sequencing. But it’s still unsettling. “A discussion has to occur with the physicians providing the test and the patients using the test and within society,” says Wapner. “When we do a microarray, we have to ask, If you have a finding of unknown significance, do you want us to tell you?”
Wapner and his colleagues argue that if the 1.7% benefit in identifying disease-linked genetic changes is confirmed, then that should be enough to offer the technique to all pregnant women. But getting the test should also include greater reliance on genetic counselors to help expectant parents make sense of their results. “It’s important that parents understand that not every unknown change in DNA definitely means disease will develop,” says Klugman. “At this point in time, we can’t predict. All we can do is hope to educate.”