Skip to main content
Premium Trial:

Request an Annual Quote

Prenatal Exome Sequencing Improves Genetic Diagnosis for Fetal Structural Anomalies

NEW YORK (GenomeWeb) – Adding whole-exome sequencing to the suite of prenatal diagnostics could boost the number of cases for which a genetic diagnosis is found, according to two new studies.

Ultrasounds uncover fetal anomalies in about 3 percent of pregnancies and follow-up testing by karyotyping and chromosomal microarray analysis finds that a third of these cases have an abnormal karyotype and a further 6 percent a disease-associated copy number variation.

A pair of studies appearing in the Lancet examined whether prenatal whole-exome sequencing could improve genetic diagnoses in fetuses with anomalies found via ultrasound. After parent-fetus trio exome sequencing and analysis, the two studies came to similar results: the addition of sequencing could uncover a clinically significant variant in about 8 to 12 percent of fetuses.

"Based on our findings, whole-exome sequencing could serve as a valuable addition to standard prenatal genetic tests, with the potential to improve perinatal care for infants with genetic conditions and ease parents' fears by offering a clear diagnosis," Ronald Wapner, director of reproductive genetics at Columbia University's Institute for Genomic Medicine and senior author of one of the papers, said in a statement.

For their study, Wapner and his colleagues sequenced 234 parent-fetus trios with normal karyotype and chromosomal microarray results where the fetus had a structural anomaly. They generated an exome-wide average read coverage of 89.3 and screened the data for pathogenic variants.

After a consensus agreement process, the researchers reported that 24 of the 234 fetuses had a diagnostic genetic variant, one that was either pathogenic or likely pathogenic — a diagnostic rate of 10 percent. Of these, 63 percent were de novo mutations, though three were autosomal dominant mutations inherited from an undiagnosed parent.

Additionally, the researchers considered variants that have yet to be conclusively tied to disease, though they occur at a higher frequency in developmental disorders compared to the general population. The addition of these variants, the researchers said, could further boost the diagnostic yield in the future, as more data about them becomes known.

Similarly, researchers from the Prenatal Assessment of Genomes and Exomes (PAGE) study in the UK conducted a prospective cohort study that sequenced the exomes of 596 families, including parent-fetus trios, two sets of twins, and 14 fetus-parent dyads, where the fetus had a structural anomaly but had tested negative for aneuploidy or CNVs. They then assessed 184 genes implicated in developmental disorders to identify 321 variants that were candidate diagnostic findings.

After assessment by a clinical review panel, the researchers diagnosed 52 or 8.5 percent of the fetuses, who had likely pathogenic or pathogenic variants relevant to their structural anomaly.

The researchers also noted that two dozen additional fetuses harbored genetic variants that, while not diagnostic, warrant additional clinical and molecular investigation. Including those variants would increase the number of clinically relevant results to 76, or 12.5 percent, they said.

Both groups added that their diagnostic rate varied based on the number of structural anomalies the fetus had — fetuses with multiple anomalies had a diagnostic rate of 19 percent for Wapner's team and 15.4 percent for the PAGE team. Additionally, the diagnostic rate also varied by where those anomalies were found. For instance, they reported higher diagnostic rates among fetuses with skeletal anomalies.

Both research teams pointed out that their diagnostic rates fell below the 25 to 35 percent rates that have been observed for clinical exome sequencing in the pediatric population. They suggested that the difference could be due to their selection procedures, but also noted that their rates did increase in subpopulations.

In an accompanying commentary in the Lancet, Michael Talkowski and Heidi Rehm, both from Massachusetts General Hospital and the Broad Institute, argued that combining whole-exome sequencing and molecular cytogenetic approaches would boost diagnostic precision and improve clinical management.

"We suggest that these studies serve as the introduction of WES into prenatal testing and document a compelling justification for its adoption," they wrote. "The technology is mature, the data are reproducible, and the processes are established in many clinical laboratories."