Diagnostic Yield of Epilepsy Panels in Children With Medication-Refractory Epilepsy

Segal, Eric; Pedro, Hélio; Valdez-Gonzalez, Karen; Parisotto, Sarah; Gliksman, Felicia; Thompson, Stephen; Sabri, Jomard; Fertig, Evan

doi:10.1016/j.pediatrneurol.2016.06.019

Cited by 24 publications

(16 citation statements)

References 12 publications

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“…Furthermore, the final diagnostic yield for TGPS and WES were also similar to previous reports on neurogenetic diseases utilizing the same technologies (Jones et al, 2013;Martínez et al, 2017;Segal et al, 2016). We previously reported a diagnostic yield slightly higher using WES in a small series of patients with neurogenetic disorders (Córdoba et al, 2018).…”

Section: Discussionsupporting

confidence: 86%

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The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

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The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology. K E Y W O R D S diagnostic odyssey, mosaicism, targeted gene panel sequencing, variants of unknown significance, whole exome sequencing 1 | INTRODUCTION Neurogenetic diseases encompass a vast group of entities with marked genetic and phenotypic heterogeneity. Nowadays, the process of establishing a diagnosis for this subset of neurological conditions requires extensive clinical, radiological, and genetic evaluations, often becoming a "diagnostic odyssey" for the patient and the family (Carmichael, Tsipis, Windmueller, Mandel, & Estrella, 2015). Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might &

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Section: Discussionsupporting

confidence: 86%

“…On the other hand, the yield obtained in patients with genetic white matter abnormalities (leukodystrophies and genetic leukoencephalopathies) and epileptic encephalopathies and other epilepsies was higher than previously reported (Segal et al, 2016;Vanderver et al, 2016).…”

Section: Discussioncontrasting

confidence: 62%

The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

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“…In a group of patients with epileptic encephalopathy, use of targeted NGS panels increased the genetic diagnostic yield from <10% to >25% (Mercimek-Mahmutoglu et al 2015 ). Similarly, diagnostic yields in the range of 22–25% have been reported with the use of epilepsy gene panels (Allen et al 2016 ; Segal et al 2016 ; Mercimek-Mahmutoglu et al 2015 ).…”

Section: The Omicsmentioning

confidence: 81%

Multiomics tools for the diagnosis and treatment of rare neurological disease

Crowther

Poms

Plecko

2018

J of Inher Metab Disea

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Conventional workup of rare neurological disease is frequently hampered by diagnostic delay or lack of diagnosis. While biomarkers have been established for many neurometabolic disorders, improved methods are required for diagnosis of previously unidentified or underreported causes of rare neurological disease. This would result in a higher diagnostic yield and increased patient numbers required for interventional studies. Recent studies using next-generation sequencing and metabolomics have led to identification of novel disease-causing genes and biomarkers. This combined approach can assist in overcoming challenges associated with analyzing and interpreting the large amount of data obtained from each technique. In particular, metabolomics can support the pathogenicity of sequence variants in genes encoding enzymes or transporters involved in metabolic pathways. Moreover, metabolomics can show the broader perturbation caused by inborn errors of metabolism and identify a metabolic fingerprint of metabolic disorders. As such, using "omics" has great potential to meet the current needs for improved diagnosis and elucidation of rare neurological disease.

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“…Genetic Characteristics In Drug-resistant Epilepsy Of Published Studies Table 3 provides a summary of previous studies about genetic characteristics in DRE [12][13][14][15][16][17][18][19][20][21]. Regardless of varied molecular diagnostic tool used between studies, some gene mutations were found to appear repeatedly, such as SCN1A (5.6%, n = 74/1308), followed by SCN8A (1.37%, n = 18/1308), TSC2 (1.22%, n = 16/1308), SCN2A (1.07%, n = 14/1308) and KCNQ2 (0.99%, n = 13/1308) 3).…”

Section: Discussionmentioning

confidence: 99%

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Lin

Chou

Hong

2020

Preprint

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Background Drug-resistant epilepsy (DRE) affects 7–20% of children with epilepsy. Although some risk factors for DRE have been identified, the results have not been consistent. Moreover, data regarding the risk factors for epilepsy and its seizure outcome in the first 2 years of life are limited. Methods We analyzed data for children aged 0–2 years with epilepsy and neurodevelopmental disability (NDD) from January, 2013, through December, 2017. These patients were followed up to compared the risk of DRE in patients with genetic defect (genetic group) with that without genetic defect (nongenetic group). Additionally, we conducted a meta-analysis to identify the pooled prevalence of genetic factors in children with DRE Results A total of 96 patients were enrolled. A total of 68 patients were enrolled in the nongenetic group, whereas 28 patients were enrolled in the genetic group. The overall DRE risk in the genetic group was 6.5 times (95% confidence interval [CI], 2.15–19.6; p = 0.03) higher than that in the nongenetic group. Separately, a total of 1308 DRE patients were participated in the meta-analysis. The pooled prevalence of these patients with genetic factors was 22.8% (95% CI 17.4–29.3) Conclusions The genetic defect plays a crucial role in the development of DRE in younger children with epilepsy and NDD. The results can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE.

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Diagnostic Yield of Epilepsy Panels in Children With Medication-Refractory Epilepsy

Cited by 24 publications

References 12 publications

The odyssey of complex neurogenetic disorders: From undetermined to positive

The odyssey of complex neurogenetic disorders: From undetermined to positive

Multiomics tools for the diagnosis and treatment of rare neurological disease

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

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