Gene List Selection Matters: Missed Diagnoses in Prenatal Exome Sequencing-PanelApp R21 and HPO-Driven Versus...

To evaluate whether the causative variants found upon clinical exome sequencing in fetuses affected with selected structural anomalies would also be detected if PanelApp-R21 or Human Phenotype Ontology (HPO)-driven gene selection terms were applied instead.

During 9 years (2016-2024), the whole exome was sequenced in 206 pregnancies with selected fetal structural anomalies, with prospective interpretation of about 5000 morbid OMIM genes. Retrospectively, 79 causative and 19 incidental findings were reviewed and assessed for their detectability under two alternative strategies: PanelApp-R21 or HPO-driven gene lists.

Among the 79 causative genes identified by interpreting morbid OMIM genes in 78 structurally abnormal fetuses, PanelApp-R21 was able to detect 76 (96%) genes, while HPO-driven terms identified only 56 (71%). For 19 incidental findings, the PanelApp-R21 pathway could identify eight (42%), while HPO terms captured only one (5.3%).

In prenatal ES, reliance on HPO-driven gene selection significantly lowers diagnostic yield compared with clinical ES, with nearly one-third of primary findings and most incidental findings missed. PanelApp represents a pragmatic alternative, preserving a high primary diagnostic yield while limiting incidental findings.