Next Generation Sequencing Methods for Diagnosis of Epilepsy Syndromes

Dunn, Paul J.; Albury, Cassie L.; Maksemous, Neven; Benton, Miles C.; Sutherland, Heidi G.; Smith, Robert A.; Haupt, Larisa M.; Griffiths, Lyn R.

doi:10.3389/fgene.2018.00020

Cited by 112 publications

(104 citation statements)

References 113 publications

(143 reference statements)

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“…However, clinicians must be cognizant of variability in panels offered by different companies, as well as the potential challenges in interpretation. The number of genes tested varies between companies, ranging from less than 100 to well over 400, as does coverage . The latter means, simply put, that there may be a higher or lower chance of a variant being missed depending on how well a given panel interrogates specific regions of the genome.…”

Section: Discussionmentioning

confidence: 99%

“…The number of genes tested varies between companies, ranging from less than 100 to well over 400, as does coverage. 25,26 The latter means, simply put, T A B L E 1 (Continued) that there may be a higher or lower chance of a variant being missed depending on how well a given panel interrogates specific regions of the genome. In our study, there was no significant yield difference between the smaller panel analyzing 126 genes versus broader coverage including up to 185 genes (P = .57).…”

Section: Discussionmentioning

confidence: 99%

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Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

et al. 2019

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Objective To determine the diagnostic yield of a commercial epilepsy gene panel in adults with chronic epilepsy and accompanying intellectual disability, given that genetic evaluation is often overlooked in this group of patients. Methods This is a cross‐sectional study analyzing the results of epilepsy gene panels including up to 185 genes in adult epilepsy patients with intellectual disability, according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Patients with acquired structural brain abnormalities or known chromosomal abnormalities were excluded. Results From approximately 600 patients seen from January 2017 to June 2018 at a single academic epilepsy center, 64 probands and two affected relatives (32 males, mean age = 31 years ± 10) were selected and clinically tested. Fourteen probands (14/64 = 22%; four males, mean age = 32 years ± 10) were found to have pathogenic or likely pathogenic variants in the following genes: SCN1A, GABRB3, UBE3A, KANSL1, SLC2A1, KCNQ2, SLC6A1, HNRNPU, STX1B, SCN2A, PURA, and CHD2. Six variants arose de novo, and the inheritance was not determined in eight. Nine probands (64%) had severe or profound intellectual disability, and five (35%) had autistic features. Eight patients (57%) had a diagnostic change from presumptive clinical diagnosis prior to genetic testing. Significance We were able to demonstrate that a commercial epilepsy gene panel can be an important resource in clinical practice, identifying the etiology in 22% of adults with epilepsy and intellectual disability. The diagnostic yield is similar to previously reported pediatric cohorts. Larger samples would be required to evaluate the more prevalent genotypes among adult epilepsy patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

et al. 2019

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“…[1][2][3] Aside from determining prognosis and recurrence risk, the identification of a genetic etiology can guide strategies for clinical management in certain forms of epilepsy, providing powerful opportunities for precision medicine. [1][2][3] Aside from determining prognosis and recurrence risk, the identification of a genetic etiology can guide strategies for clinical management in certain forms of epilepsy, providing powerful opportunities for precision medicine.…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10] This is particularly important in early-onset epilepsies, several of which are good candidates for precision medicine but in current standard practice do not attract the requisite urgent attention. 2,[12][13][14][15][16][17] Accurate interpretation of clinically important variants can be challenging amid naturally existing variation in epilepsyrelated genes. 2,[12][13][14][15][16][17] Accurate interpretation of clinically important variants can be challenging amid naturally existing variation in epilepsyrelated genes.…”

Section: Introductionmentioning

confidence: 99%

Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy

et al. 2019

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Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.

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“…It often takes many years before a patient receives a correct diagnosis or the appropriate medication . Research to elucidate molecular mechanisms of epilepsy is now reaching the clinic, with gene panels and exome/genome sequencing guiding some treatment and care pathways . However, the majority of patients still do not receive a genetic diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Advancing research toward faster diagnosis, better treatment, and end of stigma in epilepsy

et al. 2019

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Seven large European Union (EU)–funded epilepsy‐related research projects joined forces in May 2018 in Brussels, Belgium, in a unique community building event—the epiXchange conference. During this conference, 170 investigators from the projects DESIRE, EpimiRNA, EPISTOP, EpiTarget, EpiXchange, and EpiPGX as well as the European Reference Network EpiCARE, met up with key stakeholders including representatives of the European Commission, patient organizations, commercial partners, and other European and International groups. The epiXchange conference focused on sharing and reviewing the advances made by each project in the previous 5 years; describing the infrastructures generated; and discussing the innovations and commercial applications across five thematic areas: biomarkers, genetics, therapeutics, comorbidities, and biobanks and resources. These projects have, in fact, generated major breakthroughs including the discovery of biofluid‐based molecules for diagnosis, elucidating new genetic causes of epilepsy, creating advanced new models of epilepsy, and the pre‐clinical development of novel compounds. Workshop‐style discussions focused on how to overcome scientific and clinical challenges for accelerating translation of research outcomes and how to increase synergies between the projects and stakeholders at a European level. The resulting advances would lead toward a measurable impact of epilepsy research through better diagnostics, treatments, and quality‐of‐life for persons with epilepsy. In addition, epiXchange provided a unique forum for examining how the different projects could build momentum for future novel groundbreaking epilepsy research in Europe and beyond. This report includes the main recommendations that resulted from these discussions.

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Next Generation Sequencing Methods for Diagnosis of Epilepsy Syndromes

Cited by 112 publications

References 113 publications

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy

Advancing research toward faster diagnosis, better treatment, and end of stigma in epilepsy

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