Novel variants in established epilepsy genes in focal epilepsy

Maša Kovačević; Ognjen Milićević; Marija Branković; Milena Janković; Ivana Novaković; Dragoslav Sokić; Aleksandar Ristić; Jannah Shamsani; Nikola Vojvodić

doi:10.1016/j.seizure.2023.06.005

Novel variants in established epilepsy genes in focal epilepsy

Seizure. 2023 Aug:110:146-152. doi: 10.1016/j.seizure.2023.06.005. Epub 2023 Jun 7.

Authors

Maša Kovačević¹, Ognjen Milićević², Marija Branković², Milena Janković³, Ivana Novaković², Dragoslav Sokić⁴, Aleksandar Ristić⁴, Jannah Shamsani⁵, Nikola Vojvodić⁴

Affiliations

¹ Neurology Clinic, University Clinical Center of Serbia, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: massa.kovacevic@gmail.com.
² Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
³ Neurology Clinic, University Clinical Center of Serbia, Belgrade, Serbia.
⁴ Neurology Clinic, University Clinical Center of Serbia, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
⁵ GenieUs Genomics, Darlinghurst, Australia.

PMID: 37390664
DOI: 10.1016/j.seizure.2023.06.005

Abstract

Introduction: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers.

Patients and methods: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria.

Results: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1.

Conclusion: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.

Keywords: DEPDC5; Epilepsy genetics; Focal epilepsy; GRIN2A; PCDH19; SCN1A.

MeSH terms

Adult
Child
Epilepsies, Partial* / diagnosis
Epilepsies, Partial* / genetics
Epilepsy* / diagnosis
Epileptic Syndromes* / genetics
Genetic Testing
Humans
Intellectual Disability* / genetics
Protocadherins

Substances

PCDH19 protein, human
Protocadherins