Her 2015 studycompared the accuracy of trisomy screening with cell-free DNA to standard ultrasound (crown-to-rump length and nuchal translucency) in trisomies 21, 18, and 13. For trisomy 21, specificity was similar between the methods (99% vs. 95%), but sensitivity was significantly better (100% vs. 79%). Negative predictive value was similar as well (about 100% for each method), but the cell-free DNA blood test performed significantly better in terms of positive predictive value (81% vs. 3%).
Cell-free DNA testing also performed better for trisomies 18 and 13, although the results were not as dramatic.
Accurate, low-risk prenatal genetic testing is a must, Dr. Norton said. A 2014 study of 31,000 pregnancies illustrated this. Cell-free DNA testing found 507 fetuses with high-risk results; 6% of these pregnancies were terminated without confirmatory karyotyping. “This is disconcerting,” especially if the positive predictive value is not high, she said.
If large-scale screening were implemented, even a 1% false-positive rate could spur sobering consequences. That would flag 1,000 at-risk fetuses in every 100,000 tests. Assuming that the positive predictive value was 68%, if 6% of these pregnancies were terminated without karyotype confirmation, 20 normal fetuses could be aborted, Dr. Norton estimated.
Fine-tuning noninvasive tests
Dr. Wapner is confident that maternal blood testing will quickly become a fine-tuned instrument for detecting fetal aneuploidy, and that it will become an accepted part of prenatal care. It can be extremely helpful in the cases of de novo mutations – the completely unpredictable chromosomal abnormalities that account for more than 90% of genetic defects. Some of these problems can be corrected soon after birth, and some can even be treated or eliminated prenatally. And those that can’t, he said, could be detected in plenty of time to allow careful consideration of how to proceed with a pregnancy.
Brown-Vialetto-Van Laere syndrome 2 (BVVLS2) is an excellent example of this potential, said panel member David Goldstein, Ph.D., of Columbia University, New York. He described one of his patients, an 18-month-old girl who would have died if whole-exome sequencing had not identified this as the cause of her devastating neuromuscular decline.
BVVLS2 is caused by a mutation of the SLC52A2 and SLC52A3 genes, which encode for proteins that facilitate transmembrane riboflavin transport. The disorder is exceedingly rare: only 90 cases have been recorded. It’s also exceedingly hard to diagnose, since it presents a panoply of symptoms including sensorineural deafness; breathing problems; muscle weakness in the face, neck, shoulders, and limbs; spasticity and exaggerated reflexes. It presents at various times, progresses rapidly, and is typically fatal.
However, BVVLS2 can be quite simple to treat using high doses of riboflavin. The aim is to keep circulating levels so high that some of the vitamin does end up in cells, usually transported by alternative pathways, said Dr. Goldstein.
The patient presented with sudden-onset nystagmus and was initially diagnosed with an unspecified autoimmune disorder. But she failed to respond to corticosteroids and cyclophosphamide. She developed rapidly progressing neuromuscular symptoms, including gait difficulty, head tilt, and drooling.
Whole-exome sequencing identified the inherited BVVLS2 mutation. She was immediately started on high-dose oral riboflavin, with improvement noted in 2 weeks. She continues to improve and be on target with all her developmental milestones, Dr. Goldstein said.
This is a perfect example of a case where prenatal diagnosis could have resulted in early treatment, avoiding all of the problems this patient experienced, Dr. Wapner said.
“This kind of testing lets us move beyond having only two options – keep or terminate. It really is the beginning of personalized medicine for the fetus,” Dr. Wapner said.
None of the researchers mentioned in this article reported having any relevant financial disclosures.
Watch a video interview on the future of prenatal genetic screening here.