Gene Panel Versus Whole Exome Sequencing for Fetal Anomalies

Exome sequencing (ES) and gene panels can be considered for fetal anomalies. Whether ES offers substantial benefit over targeted panels is not clear.

Secondary analysis of a prospective cohort study of pregnancies with fetal anomalies undergoing ES. We included cases with isolated or multisystem skeletal dysplasias, CNS anomalies, and/or cardiac anomalies. Participants underwent ES, and pathogenic (P) and likely pathogenic (LP) variants were reported. The primary outcome was the percentage of P/LP variants found on ES that would have been identified on panels available prenatally in the United States.

109 cases with relevant anomalies were included in the primary analysis. Of these, 20 (18%) had P/LP variant(s) identified on ES-4 multisystem, 4 isolated CNS, 6 isolated cardiac, and 6 isolated skeletal dysplasia. Gene panels would have detected 50 (88%) of the variants identified by ES. Yield was highest for isolated skeletal anomalies (100%) compared to CNS and cardiac malformations (75% and 67%, p = 0.02). Yield was higher for isolated anomalies than multisystem anomalies (median 91.5% vs. 50%, p < 0.01).

In cases of fetal anomalies with genetic etiologies identified on ES, commercial gene panels had variable diagnostic yields. Panels performed worst for multisystem anomalies.