Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

PLoS One 2021 Sep 1;16(9):e0255933. doi: 10.1371/journal.pone.0255933.

PMID: 34469436

Kimberly Gall, Emanuela Izzo, Eija H Seppälä

Highlights: This study supports comprehensive genetic testing for patients whose first seizure occurs ≥ 24 months of age. It also supports early application of testing in this age group, as the identified diagnoses can have significant impact on patient management and outcome.

Abstract

Background: Epilepsy is one of the most prevalent neurological diseases that develops in childhood and has a hereditary cause. The possibility for etiologically-based management and therapy is enhanced by genetic diagnosis. Early-onset (<24 months) epilepsies have been the focus of previous studies; evidence on later-onset epilepsies is scarce.

Objective: The purpose of this study was to see if a clinically accessible epilepsy panel might reduce the age of diagnosis of neuronal ceroid lipofuscinosis type 2 in a pediatric epilepsy cohort with epilepsy onset between 24 and 60 months of life (CLN2).

Methods: The researchers employed epilepsy panels based on next-generation sequencing (NGS), which included genes linked to epileptic encephalopathies and inborn errors of metabolism (IEMs) that manifest as epilepsy. The identification of copy-number variants (CNVs) using NGS data was included. The American College of Medical Genetics and Genomics (ACMG) provided recommendations for variant interpretation.

Results: The study included 211 individuals who were between the ages of 24 and 60 at the time of enrolment, had their first unprovoked seizure at or after 24 months, and had at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. The median age at testing was 42 months, and the median age at the beginning of the first seizure was 30 months; the average time between the first seizure and thorough genetic testing was 10.3 months. In 43 individuals, a genetic diagnosis was found (20.4%). CNVs were found in 25.6% of diagnosed individuals, including 27.3% of intragenic CNVs. An IEM was diagnosed in 11 (25.6%) of the individuals in the diagnostic cohort. CLN2 was the most common molecular diagnosis (14% of diagnosed patients). These individuals were diagnosed 12-24 months sooner than the normal course of the disease indicated.

Conclusions: This research backs detailed genetic testing for patients who have their first seizure after the age of 24 months. It also encourages the use of testing in this age range early on, because the diagnosis identified can have a substantial influence on patient management and prognosis.

Keywords: Neuronal ceroid lipofuscinosis type 2, CLN2, epilepsy