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

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...

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Autores principales:	Kimberly Gall, Emanuela Izzo, Eija H Seppälä, Kirsi Alakurtti, Lotta Koskinen, Inka Saarinen, Akashdeep Singh, Samuel Myllykangas, Juha Koskenvuo, Tero-Pekka Alastalo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0f7f4798607340f6af812a41cc79a33b
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spelling	oai:doaj.org-article:0f7f4798607340f6af812a41cc79a33b2021-12-02T20:08:44ZNext-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.1932-620310.1371/journal.pone.0255933https://doaj.org/article/0f7f4798607340f6af812a41cc79a33b2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255933https://doaj.org/toc/1932-6203Epilepsy 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.Kimberly GallEmanuela IzzoEija H SeppäläKirsi AlakurttiLotta KoskinenInka SaarinenAkashdeep SinghSamuel MyllykangasJuha KoskenvuoTero-Pekka AlastaloPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0255933 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kimberly Gall Emanuela Izzo Eija H Seppälä Kirsi Alakurtti Lotta Koskinen Inka Saarinen Akashdeep Singh Samuel Myllykangas Juha Koskenvuo Tero-Pekka Alastalo Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
description	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.
format	article
author	Kimberly Gall Emanuela Izzo Eija H Seppälä Kirsi Alakurtti Lotta Koskinen Inka Saarinen Akashdeep Singh Samuel Myllykangas Juha Koskenvuo Tero-Pekka Alastalo
author_facet	Kimberly Gall Emanuela Izzo Eija H Seppälä Kirsi Alakurtti Lotta Koskinen Inka Saarinen Akashdeep Singh Samuel Myllykangas Juha Koskenvuo Tero-Pekka Alastalo
author_sort	Kimberly Gall
title	Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
title_short	Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
title_full	Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
title_fullStr	Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
title_full_unstemmed	Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.
title_sort	next-generation sequencing in childhood-onset epilepsies: diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (cln2) disease diagnosis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/0f7f4798607340f6af812a41cc79a33b
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Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis.

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