Use of Clinically Informed Strategies and Diagnostic Yields of Genetic Testing for Fetal Structural Anomalies...

To investigate the performance of targeted gene sequencing, expanded gene panels, and selected exomes for prenatally identified fetal anomalies, after non-diagnostic microarray results.

All fetal samples received for genetic testing for fetal structural anomalies in the Canadian Maritime Provinces (2014-2022) were identified. Utilization and results of NGS sequencing strategies after a non-diagnostic microarray were correlated with ultrasound findings and autopsy results.

Five hundred and ninety-three cases of fetal anomalies with non-diagnostic RAD results were identified, including 319 (54%) with isolated anomalies. Diagnostic yield from the microarray was 7.5%. Sequence-based testing for 131 cases gave an overall diagnostic yield of 38% (8.4% of initial cohort). For isolated anomalies, diagnostic yield was highest in the intracranial, renal, and musculoskeletal systems (44%, 60%, 64% respectively). Appropriate targeted gene sequencing provided a diagnostic yield of 40%. With clinically indicated criteria for exome analysis, diagnostic yields were higher than when clinical information prompted use of a selected gene panel (73% vs. 27%). Expanding to an exome after a non-diagnostic gene panel had an additional diagnostic yield of 13%.

Multidisciplinary review and comprehensive clinical information can inform the selection of strategies for expanded genetic testing after non-diagnostic microarray for fetal anomalies within a publicly funded health care system.