Use of Clinically Informed Strategies and Diagnostic Yields of Genetic Testing for Fetal Structural Anomalies Following a Non-Diagnostic Microarray Result: A Population-Based Cohort Study.

OBJECTIVE

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

METHOD: 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.

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%.

CONCLUSION

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.