Gene Panel Versus Whole Exome Sequencing for Fetal Anomalies

OBJECTIVE: Exome sequencing (ES) and gene panels can be considered for fetal anomalies. Whether ES offers substantial benefit over targeted panels is not clear. METHODS: 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. RESULTS: 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). CONCLUSIONS: In cases of fetal anomalies with genetic etiologies identified on ES, commercial gene panels had variable diagnostic yields. Panels performed worst for multisystem anomalies.