Review of Commercially Available Epilepsy Genetic Panels

Chambers, Chelsea; Jansen, Laura A.; Dhamija, Radhika

doi:10.1007/s10897-015-9906-9

Cited by 50 publications

(51 citation statements)

References 10 publications

(11 reference statements)

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“…Both assessed HTS panels were cost‐effective compared to the standard diagnostic model with a cost saving of AU$7,535 (95% CI: $2,278; $22,188) and AU$16,387 (95% CI: $9,782; $35,120) per additional diagnosis (Table and Figure ). The anticipated diagnostic yields reflect recent similar reported results (Mercimek‐Mahmutoglu et al., ; Trump et al., ), and demonstrated that a larger number of genes in a panel did not equate to a higher diagnostic yield, reflecting the importance of a tightly curated gene list (Chambers et al., ). For example, not all panels included the recently described EE genes DNM1 (616346), DYNC1H1 (614563), and WWOX (616211).…”

Section: Discussionsupporting

confidence: 81%

“…Although the cost of ES is falling, limited diagnostic budgets and concerns regarding the chance of detecting an incidental finding (IF) may mean that families and clinicians prefer to order a HTS gene panel (Chambers et al., ) over ES. Simpler genetic counseling (with a time and cost saving) is required for a panel than ES (Chambers et al., ). We therefore compared the cost and anticipated diagnostic yield of two commercial HTS EE panels with the SDM.…”

Section: Discussionmentioning

confidence: 99%

“…No incidental findings (IF) were detected in the course of our study, unsurprisingly given the size of our cohort (Amendola et al., ; Olfson et al., ). IF can also result from HTS panels, for example, due to the overlap between cardiac arrhythmia and epilepsy genes (Chambers et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…OMIM currently lists 56 genetic causes of infantile onset EE (source: Online Mendelian Inheritance in Man website accessed June 2017, http://www.omim.org/phenotypicSeries/PS308350), but there are well over 200 monogenetic conditions in which EE has been reported (Gursoy & Ercal, ). However, there is now a substantial body of work demonstrating that application of high‐throughput sequencing (HTS) via targeted multigene panels or exome sequencing (ES) improves diagnostic yield in EE by 20%–40% (Chambers, Jansen, & Dhamija, ; Consortium E‐R, Project EPG, Consortium EK, ; Helbig et al., ; Kwong et al., ; Lemke et al., ; Trump et al., ); HTS has the potential to minimize this invasive and expensive “diagnostic odyssey.” Most reports claim that this implies cost effectiveness (Helbig et al., ; Lemke et al., ), but solid health economic data are lacking.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Palmer

Schofield

Shrestha

et al. 2018

Molec Gen & Gen Med

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BackgroundEpileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.MethodsWe conducted a retrospective cost‐effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well‐phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first‐tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.ResultsThe diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost‐effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost‐effective. The clinical utility of all diagnoses was reported.ConclusionOur study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Palmer

Schofield

Shrestha

et al. 2018

Molec Gen & Gen Med

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“…Recently, targeted capture using NGS panels have been used in both research and clinical molecular genetics laboratories to understand the molecular etiology of epilepsy disorders53. The NGS panels used in research studies vary in gene composition, sample size, inclusion criteria, and sequence analytic protocol.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Wang

Rao

et al. 2017

Sci Rep

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Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children.

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Genetics of Epileptic Encephalopathies

Palmer

Sachdev

Macintosh

et al. 2017

Encyclopedia of Life Sciences

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Epileptic encephalopathy (EE) is a descriptive term for a group of severe epilepsy disorders characterised predominantly by early onset drug‐resistant seizures, accompanied by developmental stagnation or regression secondary to epileptiform activity. The aetiological diagnosis of EE is challenging, as causes are numerous with significant phenotypic overlap: these include acquired causes as well as numerous de novo or inherited monogenic seizure disorders, genetic inborn errors of metabolism, intellectual disability syndromes and chromosomal aberrations. A diagnostic pathway should include consultation with a Paediatric Neurologist and Clinical Geneticist, screening for immediately treatable causes, neuroimaging and electroencephalogram (EEG) and genetic testing including chromosomal microarray and consideration of a next generation sequencing technique that can interrogate multiple genetic causes, such as a multigene panel, or exome/genome sequencing. Understanding the underlying genetic cause of EE can allow accurate genetic counselling for the family and providing personalised management and support. Key Concepts EE is a descriptive term for a group of disorders where epileptiform activity itself contributes to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology. Although EE can be acquired, most cases of previously considered cryptogenic EE are now recognised to be due to single gene disorders. The majority of monogenic EE are due to de novo pathogenic variants: however, up to 10% of EE may be due to X‐linked or autosomal recessive conditions, with higher rates in populations where consanguineous marriage is more common. Although there are some genotype/phenotype correlations, a single genetic cause can result in a variety of EE and non‐EE phenotypes, and each subtype of EE can have a variety of genetic causes. Genetic heterogeneity in EE limits the value of targeted genetic testing. An optimal, cost‐effective diagnostic approach involves first‐tier tests that target common and treatable conditions, followed by second‐tier tests including sequencing of a panel of genes known to cause EE or exome/whole genome sequencing to allow genome‐wide interrogation. Factors influencing choice of type of genetic test (multigene panel versus exome/genome sequencing) include epilepsy semiology, developmental regression, additional neurological or extra‐cerebral manifestations, family history and clinician and patient choice and cost. Phenotypic factors that suggest exome/genome sequencing may be valuable and include developmental regression and progressive features, multiorgan involvement including dysmorphism, additional neurological features and cerebral malformations. Evaluation of the likely pathogenicity of a novel genetic variant should include consideration of similarity with the types of genetic variants previously identified as causal of EE for that gene, including which functional domain(s) are implicated as well as overlap with the associated clinical features previously described for that condition. For variants remaining of uncertain clinical significance, ongoing pathogenicity assessment will be required in the light of advances in the understanding of the genetics of EE.

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Review of Commercially Available Epilepsy Genetic Panels

Cited by 50 publications

References 10 publications

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Genetics of Epileptic Encephalopathies

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