From diagnosis to treatment in genetic epilepsies: Implementation of precision medicine in real-world clinical practice

Matthias De Wachter; An-Sofie Schoonjans; Sarah Weckhuysen; Kristof Van Schil; Ann Löfgren; Marije Meuwissen; Anna Jansen; Berten Ceulemans

doi:10.1016/j.ejpn.2023.11.003

From diagnosis to treatment in genetic epilepsies: Implementation of precision medicine in real-world clinical practice

Eur J Paediatr Neurol. 2024 Jan:48:46-60. doi: 10.1016/j.ejpn.2023.11.003. Epub 2023 Nov 22.

Authors

Matthias De Wachter¹, An-Sofie Schoonjans², Sarah Weckhuysen³, Kristof Van Schil⁴, Ann Löfgren⁴, Marije Meuwissen⁴, Anna Jansen⁵, Berten Ceulemans²

Affiliations

¹ Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Drie eikenstraat 655, 2650, Edegem, Belgium. Electronic address: matthias.dewachter@uza.be.
² Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Drie eikenstraat 655, 2650, Edegem, Belgium.
³ Department of Neurology, Antwerp University Hospital, University of Antwerp, Drie eikenstraat 655, 2650, Edegem, Belgium; Applied&Translational Neurogenomics Group, VIB-CMN, VIB, UAntwerpen, Universiteitsplein 1, 2610, Wilrijk, Belgium; Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
⁴ Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, Drie eikenstraat 655, 2650, Edegem, Belgium.
⁵ Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Drie eikenstraat 655, 2650, Edegem, Belgium; Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

PMID: 38039826
DOI: 10.1016/j.ejpn.2023.11.003

Abstract

The implementation of whole exome sequencing (WES) has had a major impact on the diagnostic yield of genetic testing in individuals with epilepsy. The identification of a genetic etiology paves the way to precision medicine: an individualized treatment approach, based on the disease pathophysiology. The aim of this retrospective cohort study was to: (1) determine the diagnostic yield of WES in a heterogeneous cohort of individuals with epilepsy referred for genetic testing in a real-world clinical setting, (2) investigate the influence of epilepsy characteristics on the diagnostic yield, (3) determine the theoretical yield of treatment changes based on genetic diagnosis and (4) explore the barriers to implementation of precision medicine. WES was performed in 247 individuals with epilepsy, aged between 7 months and 68 years. In 34/247 (14 %) a (likely) pathogenic variant was identified. In 7/34 (21 %) of these individuals the variant was found using a HPO-based filtering. Diagnostic yield was highest for individuals with an early onset of epilepsy (39 %) or in those with a developmental and epileptic encephalopathy (34 %). Precision medicine was a theoretical possibility in 20/34 (59 %) of the individuals with a (likely) pathogenic variant but implemented in only 11/34 (32 %). The major barrier to implementation of precision treatment was the limited availability or reimbursement of a given drug. These results confirm the potential impact of genetic analysis on treatment choices, but also highlight the hurdles to the implementation of precision medicine. To optimize precision medicine in real-world practice, additional endeavors are needed: unifying definitions of precision medicine, establishment of publicly accessible databases that include data on the functional effect of gene variants, increasing availability and reimbursement of precision therapeutics, and broadening access to innovative clinical trials.

Keywords: (mono)genetic epilepsy; Diagnostic yield; Precision medicine; Whole exome sequencing.

MeSH terms

Epilepsy* / diagnosis
Epilepsy* / drug therapy
Epilepsy* / genetics
Epilepsy, Generalized* / genetics
Genetic Testing / methods
Humans
Infant
Precision Medicine
Retrospective Studies