Mosaic cells can muddy NIPS results

see Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results

A recent retrospective study of nearly 53,000 prenatal tests for common fetal chromosomal abnormalities un-derscores the need for clarity when offering noninvasive prenatal screening (NIPS) to pregnant women. Grati et al. found that fetoplacental mosaicism, in which placental and fetal cells differ in containing aneuploid cells, can result in small but measurable rates of both false-positive and false-negative findings. The study, which ana-lyzed the results from a large database of prenatal testing cases in which NIPS results were confirmed by direct testing of placental and fetal DNA, showed that for the common trisomies (13, 18, and 21) false-positives can be expected in 1 in 3,006 cases and false-negatives can be expected in 1 in 107. The potential for false results led the authors to suggest that those offering NIPS counsel patients that the tissue being sampled is of placental origin and thus may not perfectly reflect the status of the fetus. To ensure that patients understand the implica-tions of fetal-placental mosaicism, the authors propose that the term "cell-free fetal DNA" be changed to "cell-free placental DNA." The change in terminology should help providers inform patients of the test's limitations and the potential need for confirmatory invasive testing. —Karyn Hede, News Editor

NIPT extended to diagnosis of single-gene recessive disorder

see Integration of targeted sequencing and NIPT into clinical practice in a Chinese family with maple syrup urine disease

A Chinese research team has applied a combination of massively parallel sequencing and noninvasive prenatal testing to diagnose a single-gene autosomal recessive disorder within a clinically actionable time frame. The report presents a proof-of-principle clinical case showing the potential for noninvasive prenatal testing (NIPT) to be useful in diagnosing Mendelian disorders in the prenatal setting. In this case, the researchers worked with parents known to be carriers of maple syrup urine disease (MSUD), an autosomal recessive metabolic disorder with at least 40 known genetic variants in four genes that constitute an enzyme complex essential for breaking down branched-chain amino acids. The family had one infant diagnosed with MSUD, and the mother was preg-nant again. Sequencing revealed a shared exon duplication in the affected child and the father, as well as a mu-tation, c.392A>G, in the BCKDHA gene in the affected child and the mother. The novel missense mutation was expected to be deleterious, in part because it appeared in a highly evolutionarily conserved region of the gene. Prenatal NIPT revealed that the fetus had inherited the same defective alleles that the affected child had. The researchers confirmed the findings with amniocentesis. The testing took 50 days, with a definitive diagnosis made in the twentieth week of pregnancy. —Karyn Hede, News Editor