Noninvasive Prenatal Technique Detects Subchromosomal Abnormalities

Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has allowed accurate prenatal diagnosis of aneuploidy without requirement of an invasive procedure and this approach has gained increasing clinical acceptance.

A novel technique has been developed that uses a semiconductor sequencing platform to identify small chromosomal deletions or duplications, such as occur in Cri du Chat Syndrome and DiGeorge Syndrome, with a simple blood test from the expectant mother.


An international team of scientists including those at the University of California, San Diego School of Medicine (La Jolla, CA, USA) analyzed blood plasma from 1,476 pregnant women with fetal structural abnormalities detected by ultrasound. These women also underwent an invasive diagnostic procedure and conventional fetal DNA analysis. The scientists compared that information to semiconductor sequencing results on circulating fetal DNA obtained from a blood test on the pregnant women at an average gestational age of 24 weeks.

After DNA extraction, a comparative genomic hybridization analysis (aCGH) was performed using Agilent commercial arrays (Agilent Technologies; Santa Clara, CA, USA). To obtain complete sequences of cell-free DNA (cfDNA) fragments, sequencing was performed using an Ion Proton Sequencer (Life Technologies; Carlsbad, CA, USA). The new semiconductor sequencing method detected 69 of 73 (94.5%) abnormalities of a certain size (greater than one million base pairs) detected by the conventional method. According to the investigators, the cost of NIPT with semiconductor sequencing has the potential to be less expensive than the conventional, invasive prenatal testing method, especially as genetic sequencing technologies continue to decrease in cost.

In the study, semiconductor sequencing detected 55 false positives, of which 35 (63.6%) were due to maternal, rather than fetal, chromosomal abnormalities. That means the new method will require a validation test to screen out maternal abnormalities. NIPT with semiconductor sequencing also needs to be tested at early time points in the pregnancy, at 12 to 16 weeks, and it is hoped to further improve the technique to be able to detect even smaller genetic abnormalities.

The authors concluded that methods they developed can be applied to any mixed biological sample to determine the subchromosomal abnormalities in the minor component, even when this fraction represents only a small percentage of the total DNA. In prenatal diagnostics, samples obtained from chorionic villi could be analyzed for mosaic karyotypes or maternal contamination. The study was published on November 11, 2015 in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

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University of California, San Diego School of Medicine
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