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

Abstract

Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited. The goal of this study was to determine the diagnostic yield of a clinically available epilepsy panel in a selected pediatric epilepsy cohort with epilepsy onset between 24–60 months of life and evaluate whether this approach decreases the age of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2). Next-generation sequencing (NGS)-based epilepsy panels, including genes associated with epileptic encephalopathies and inborn errors of metabolism (IEMs) that present with epilepsy, were used. Copy-number variant (CNV) detection from NGS data was included. Variant interpretation was performed per American College of Medical Genetics and Genomics (ACMG) guidelines. Results are reported from 211 consecutive patients with the following inclusion criteria: 24–60 months of age at the time of enrollment, first unprovoked seizure at/after 24 months, and at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. Median age was 42 months at testing and 30 months at first seizure onset; the mean delay from first seizure to comprehensive genetic testing was 10.3 months. A genetic diagnosis was established in 43 patients (20.4%). CNVs were reported in 25.6% diagnosed patients; 27.3% of CNVs identified were intragenic. Within the diagnosed cohort, 11 (25.6%) patients were diagnosed with an IEM. The predominant molecular diagnosis was CLN2 (14% of diagnosed patients). For these patients, diagnosis was achieved 12–24 months earlier than reported by natural history of the disease. 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.

A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease

“…TPP1 variants were the second most common in this cohort tested through the Epilepsy and Genetics Program, only less frequent than SCN1A variants ( Table 1 ). The proportion of TPP1 variants was lower than the one found by Gall et al 21 and higher than the one found by Leal-Pardinas et al 17 These differences observed between the studies are probably related to the genetic background of each population and/or different inclusion criteria.…”

“…In these cases, it is recommended that the clinician should order an epilepsy gene panel to narrow down diagnostic possibilities. 15 Pathogenic or likely-pathogenic TPP1 variants are a relatively common finding in NGS panels performed to investigate pediatric seizures, [21][22][23] emphasizing that these genetic panels can be a very useful tool to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.…”

DCX variants in two unrelated Chinese families with subcortical band heterotopia: Two case reports and review of literature

“…One of the most common clinical manifestations is epilepsy. It could occur at any age, often during the first decade but sometimes in the second or third decade and become therapy resistant [ 10 ]. Heterozygous females with germline missense or nonsense DCX variants may have no obvious brain malformations or seizures [ 11 , 12 ].…”

A microdeletion del(12)(p11.21p11.23) with a cryptic unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome

“…interacts with ATP2B2 (ATPase, Ca (2+)-Transporting, Plasma membrane, 2, MIM 108733) 55,59 , variants of which are found in patients with autism spectrum disorder 58,117 . KCNA2 (Potassium Channel, Voltage-Gated, Shaker-Related Subfamily, Member 2, MIM 176262) interacting with FAR2 55 , is associated with epileptic encephalopathy 118 and epilepsy [119][120][121][122] . Another FAR2 interacting protein, CUL3, is associated with neurodevelopmental disorders 77 and autism spectrum disorder 50 .…”