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Mosaic Maternal Fragile Site Expansion Adds to List of Variants Causing False-Positive NIPT Results

NEW YORK (GenomeWeb) – A team from the Netherlands has identified a mosaic chromosome 10 deletion, and related fragile site expansion, that can lead to false-positive results on noninvasive prenatal screens for a range of chromosomal abnormalities.

As part of the TRIDENT (Trial by Dutch Laboratories for Evaluation of Noninvasive Prenatal Testing) study, the researchers sifted through NIPS results for thousands of pregnant women, narrowing in on an unusual finding involving an apparent chromosome 10 deletion. The screen, which relied on single-read sequencing, was designed to pick up trisomies involving chromosomes 21, 18, and 13, as well as sub-chromosomal changes spanning roughly 10 megabases or more.

Through follow-up analyses on these and other cases, the team uncovered eight women with mosaic chromosome 10 deletions and expansions involving the FRA10B fragile site.

Although the deletion was not detected in the fetuses, the group warned that the mosaic maternal deletion and expansion could easily be misclassified as chromosome 10 deletions in the fetus without sufficient context.

The recurrent deletion "is a false-positive result caused by a maternal low-level mosaic deletion associated with FRA10B expansions," corresponding author Erik Sistermans, a clinical genetics researcher at VU University Medical Center, and his colleagues wrote in a paper published online yesterday in Genetics in Medicine.

"This has important consequences for clinical follow-up, as invasive procedures are unnecessary," they explained, arguing that maternal FRA10B fragile site expansion "should be added to the growing group of variants in the maternal genome that may cause false-positive NIPS results."

The team initially identified two cases with 20-megabase chromosome 10 deletions in a collection of 2,527 NIPS results, which were analyzed using the Wisecondor algorithm, tweaked to scan 250-kilobase chunks rather than megabase-sized bins. It subsequently tracked down six more cases with similar chromosome 10 deletions.

The researchers did not see the suspicious deletion in fetal DNA when they did array-based testing on amniotic fluid for four of these cases. They also could not detect the deletion with fluorescence in situ hybridization (FISH)- or SNP array-based analyses on placental or umbilical blood samples.

It wasn't until the team focused in on the nearby fragile site, FRA10B, in cultured maternal blood lymphocyte cells from a subset of the women that it narrowed in on the root of the unusual NIPS results in this region, using FISH: a fragile site expansion associated with loss of chromosome 10q telomere signal in a fraction of the cells — findings that were verified using array comparative genomic hybridization on whole blood samples from two of the women.

When it was detected, the deletion occurred in just over a tenth of cells tested. It was not found in three of the moms-to-be, the researchers explained, perhaps owing to low levels of mosaicism that were missed by array.

The authors noted that they did not test for carrier status in infants born to any of the women, since the fragile site expansion and related deletion were not linked to any clinical phenotype.

"If a deletion starting exactly at FRA10B is found, it is highly likely that it is caused by a maternal mosaic deletion associated with a repeat expansion at this fragile site," they wrote. "This repeat expansion can be confirmed by maternal testing if preferred, although there is no known phenotype linked to this fragile site, even in homozygous carriers."

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