Whole-exome sequencing combined with prenatal genetic testing helped to identify certain fetal anomalies where current testing methods could not determine the cause of the structural anomaly, researchers found.
When standard prenatal genetic testing failed to identify the cause of a structural anomaly in the fetus, adding whole-exome sequencing identified a genetic cause in an additional 10% of examined cases, reported Ronald J. Wapner, MD, of Columbia University Irving Medical Center in New York City, and colleagues.
The number of genetic anomalies in the fetus appeared to play a role, as a genetic diagnosis was achieved more frequently in those fetuses with several anomalies compared with those with only one anomaly (19% vs 6%, respectively), the authors wrote in The Lancet.
Fetal anomalies discovered via fetal ultrasound are usually followed up with karyotype testing and chromosomal microarray analysis to identify copy number variants, the authors noted, but more than 60% of pregnancies lack a definite genomic diagnosis that can guide future care and genetic counseling.
The team cited research that found that whole-exome sequencing can pinpoint a genetic cause of 25-35% of children with certain types of birth defects after negative findings in karyotype testing and chromosomal microarray.
“This result in children suggests that [whole-exome sequencing] could be an important diagnostic approach in understanding the underlying genetic causes of fetal structural anomalies, and this approach could lead to improved perinatal care and prognostic parental genetic counseling,” the authors wrote.
They explained that given the limited research on the subject, they performed a prospective cohort study that examined pregnant women with a structural anomaly in a prenatal ultrasound. The team examined data from 234 women with abnormal ultrasound findings, but where standard genetic tests were negative, they sequenced DNA from both the parents and the fetus.
Detection of diagnostic genetic variants that caused the fetal developmental anomaly via available whole-exome sequencing data was the study’s primary endpoint.
Demographically, this sample was different from other genomics studies, the authors noted, with almost three-quarters of parents self-reporting an ancestry other than European white or “sequence data placed the fetus outside principal component clusters indicative of the European white population.”
Following whole-exome sequencing, a diagnostic genetic variant was uncovered in 24 of 234 fetuses, 15 of which were de novo mutations, six from recessive genotypes, and three who were inherited in an autosomal dominant way from a previously undiagnosed parent.
Moreover, 46 fetuses had mutations that were suggestive of, but were “not confirmed to be causative of the structural anomaly,” although the authors said that under American College of Medical Genetics and Genomics guidelines, 15 of these would be considered pathogenic.
The diagnostic rate appeared to increase with increasing number of fetal anomalies on the ultrasound, with the authors noting that in fetuses with ≥3 anomalies, more than 30% had a diagnostic genetic variant.
An accompanying editorial by Michael E. Talkowski, PhD, and Heidi L. Rehm, PhD, both of Massachusetts General Hospital in Boston, said that these data indicate that for now, “a combination” of whole-exome sequencing and “molecular cytogenetic methods” will offer substantial improvements in diagnostic precision and clinical management of fetal anomalies.
They argued that this data from this study and a similar one from the same issue of The Lancet, “serve as the introduction of [whole-exome sequencing] into prenatal testing and document a compelling justification for its adoption. The technology is mature, the data are reproducible, and the processes are established in many clinical laboratories,” Talkowski and Rehm wrote.
One potential limitation of the data is that the researchers acknowledged their “limited knowledge” of in utero developmental phenotypes, which may impact their ability to confirm that “a variant identified in utero is causative and represents a genetic diagnosis.”
“Future studies are needed to determine whether performing whole-exome sequencing on fetuses during pregnancy will lead to improved care and reproductive counseling,” Wapner said in a statement.
Wapner reported having no conflicts of interest; one co-author disclosed employment with AstraZeneca.
Talkowski and Rehm are supported by grants from the National Institutes of Health; Talkowski disclosed collaboration with authors of the two studies the editorial discusses; Rehm is employed by Massachusetts General Hospital and the Broad Institute of MIT and Harvard, which both offer fee-for-service genomic testing.