Clinically significant changes in genes and variants associated with epilepsy over time: implications for re-analysis

Abstract

Abstract Despite the significant advances in understanding the genetic architecture of epilepsy, many patients do not receive a molecular diagnosis after genomic testing. Re-analysing existing genomic data has emerged as a potent method to increase diagnostic yields—providing the benefits of genomic-enabled medicine to more individuals afflicted with a range of different conditions. The primary drivers for these new diagnoses are the discovery of novel gene-disease and variants-disease relationships; however, most decisions to trigger re-analysis are based on the passage of time rather than the accumulation of new knowledge. To explore how our understanding of a specific condition changes and how this impacts re-analysis of genomic data from epilepsy patients, we developed Vigelint. This approach combines the information from PanelApp and ClinVar to characterise how the clinically relevant genes and causative variants available to laboratories change over time, and this approach to five clinical-grade epilepsy panels. Applying the Vigelint pipeline to these panels revealed highly variable patterns in new, clinically relevant knowledge becoming publicly available. This variability indicates that a more dynamic approach to re-analysis may benefit the diagnosis and treatment of epilepsy patients. Moreover, this work suggests that Vigelint can provide empirical data to guide more nuanced, condition-specific approaches to re-analysis.

Keywords

• Re-analysis of genomic data
• Epilepsy
• Genetic testing
• PanelApp
• PanelApp Australia
• ClinVar