Incorporating epilepsy genetics into clinical practice: a 360°evaluation

Area of Science:

• Genetics and Genomics
• Neurology
• Clinical Diagnostics

Background:

• Epilepsy diagnosis is challenging, particularly in early-onset and treatment-resistant cases.
• Current diagnostic pathways can be lengthy and costly, leading to significant delays in genetic diagnosis.
• Genetic factors play a crucial role in many epilepsy syndromes, necessitating advanced diagnostic approaches.

Purpose of the Study:

• To evaluate the diagnostic yield, clinical impact, and cost-effectiveness of a new epilepsy genetic diagnostic and counseling service.
• To assess the service's utility across a large UK population, focusing on patients with early-onset, treatment-resistant, or familial epilepsy.
• To compare the cost and diagnostic delay of gene panel testing versus traditional investigational pathways in neonatal epilepsy.

Main Methods:

• Development and implementation of next-generation sequencing (NGS) panels for epilepsy genetic testing.
• Clinical interpretation of results by a multidisciplinary team, including genetic counselors.
• Surveying referring clinicians and families to assess satisfaction and perceived clinical impact.
• Cost analysis of alternative investigational pathways for neonatal onset epilepsy.

Main Results:

• A genetic diagnosis was achieved in 34% of patients with seizure onset < 2 years and 4% with onset > 2 years.
• Identified pathogenic variants in key epilepsy-associated genes including SCN8A, SCN2A, SCN1A, KCNQ2, HNRNPU, GRIN2A, SYNGAP1, STXBP1, STX1B, CDKL5, CHRNA4, PCDH19, and PIGT.
• Reduced the cost of neonatal epilepsy investigations from £9362 to £2838 by implementing earlier gene panel testing.
• Significantly decreased the median diagnostic delay from 3.43 years to 21 days.
• Clinicians' pre-testing prediction of genetic diagnosis was poor, underscoring the need for comprehensive genetic testing.
• Referring clinicians and families reported high satisfaction with the service.

Conclusions:

• Epilepsy panel testing demonstrates high diagnostic yield in children with early-onset epilepsy (< 2 years).
• The service offers substantial clinical and financial benefits, significantly reducing diagnostic delays and investigation costs.
• Multidisciplinary interpretation and skilled genetic counseling are essential for effective clinical implementation and family support.