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NATIONAL HARBOR, Md. -- Genome sequencing of the fetus and both parents in pregnancies with structural anomalies pinpointed a causative genetic variant in nearly a fifth of cases in a prospective cohort study.

Patients with fetal structural anomalies were recruited for the study, and trio samples (mother, father, fetus) were sent for genomic sequencing. A previous noncausative fetal karyotype and/or chromosomal microarray was required for inclusion in the study.

Overall, 18.1% had a positive diagnosis with genomic sequencing with pathogenic/likely pathogenic (P/LP) in 15.1% and variant of uncertain significance (VUS) in 2.9%. There was single organ system involvement in 12.6% and multiple organ system involvement in 26.2%, reported Ronald Wapner, MD, of Columbia University Irving Medical Center in New York City.

Sequencing was successful in all cases with a mean turnaround time of 11.5 days (vs 13.7 days for microarray) because researchers could do the former on uncultured direct samples, Wapner explained in a presentation at the Society for Maternal-Fetal Medicine (SMFM) annual meeting.

"Because we sequenced fetuses with structural anomalies, we have demonstrated clearly that we can identify a high percentage of genetic disorders," Wapner told 番茄社区. "So the next steps will be to identify these much earlier in pregnancy, and hopefully, someday make a difference."

Wapner argued that "genome sequencing should be considered a first-tier test for the evaluation of fetal structural anomalies, and it may be appropriate to be used as a single test because genome sequencing can also give us the same information as a karyotype and a microarray."

Joanne Stone, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who wasn't involved in the research, told 番茄社区 that the study "really shows the value of this much more comprehensive genetic testing. ... I think we're going to be seeing really a lot more use of this kind of genome sequencing for fetal abnormalities, growth restriction, and things like that."

Stone also noted that insurance companies usually cover chromosomal microarray but don't often cover whole-genome sequencing. Wapner said that the cost of sequencing has dropped in recent years, and that with whole-genome sequencing, a microarray, karyotype, or cell culture can be eliminated, which will help counteract the cost.

David Hackney, MD, of Case Western Reserve University in Cleveland, told 番茄社区 that having more data can lead to a higher level of counseling for patients. "I would be surprised if 5 to 10 years from now, whole genome isn't what we're doing with those fetal cases," Hackney said.

Patients with fetal structural anomalies were recruited from five U.S. centers from August 2019 through July 2023. In total, 751 out of 5,534 screened pregnancies met inclusion criteria and consented to the study.

Inclusion criteria were presence of any fetal structural anomaly, such as isolated fetal growth restriction (if identified before 24 weeks' gestation) and nuchal translucency between 3.5-4.5 mm, as well as intention to continue on with the pregnancy based on ultrasound findings. Patients with pregnancies greater than 36 weeks' gestation and planned termination or fetal demise were excluded.

The cohort was around 60% white and highly educated; parents were in their early 30s. The most prominent anomaly was cardiac at 16.6%. Recurrent diagnoses included PTPN11 (n=8; Noonan syndrome), NIPBL (n=5; Cornelia de Lange syndrome), CHD7 (n=5; CHARGE syndrome), MYRF (n=4; cardiac urogenital syndrome), and PIEZO1 (n=4; effusion/hydrops).

Trio samples and fetal phenotypes were sent to four different study labs for genome sequencing. Positive results consistent with phenotypes were reported to the clinical team; however, VUS variants were reported at the discretion of the local study team. Local neonatologists assessed the neonate's records to determine impact to clinical care. Additionally, a committee of experts independently reviewed the genetic and neonatal results.

Among the 751 pregnancies, 84.3% were live born, as were 71.2% in the P/LP/VUS group and 89.1% in those with no variants. The delivery outcome was termination in 8.3% of cases overall, versus 19.7% of the P/LP/VUS group and 6% of the no-variants group. A total of 5.6% of the total cohort ended in miscarriage/stillbirth, as did 9.1% of the P/LP/VUS group and 5% of the no-variants group.

Wapner's group reported that among 612 liveborns with known outcomes, an overall change in the neonatal treatment plan happened in 26%, while change in care based on positive genome sequencing results happened in 70% and in 19% based on negative genome sequencing results.

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