Diagnostic Yield of Genetic Tests in Epilepsy: A Meta-Analysis and Cost-Effectiveness Study

Featuring the work of CURE Grantee Annapurna Poduri

Objective: To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.

Methods: This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing” as a point of comparison.

Results: Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33–0.57) (0.32 [95% CI: 0.22–0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18–0.29), and CMA: 0.08 (95% CI: 0.06–0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.

Conclusion: Whole-exome sequencing and epilepsy panel are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, chromosomal microarray has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

ILAE Consortium Identifies Novel Epilepsy Genes

A genome-wide analysis of nearly 45,000 people has identified 16 regions of DNA associated with epilepsy, 11 of which are newly identified.

The International League Against Epilepsy (ILAE) Consortium on Complex Epilepsies did the analysis, which involved DNA from 15,212 people with epilepsy and 29,677 people without the condition. It is the largest study of its kind. The analysis was published in the Dec 10, 2018 issue of Nature Communications.

Most of these identified genes are associated with generalized epilepsy. The genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin B6 metabolism enzyme.

Compared with focal epilepsies, generalized epilepsies appear to have a stronger heritable component. However, fewer single genes have been implicated in generalized epilepsies.

Epilepsy Research Findings: December 2018

Exciting epilepsy research discoveries include two groundbreaking studies. Dr. Steven Petrou created “minibrains” using stem cells to better understand how neurons behave in children with epilepsy. Dr. Harald Sontheimer discovered the previously unknown function of perineuronal nets, which may lead to new treatments for acquired epilepsy. Both Dr. Petrou and Dr. Sontheimer are CURE grantees, and we’re thrilled to see these innovations from them beyond the work they do with us!

In diagnostic news regarding children with epilepsy, scientists are calling for parents to have their children’s genes reviewed at least every two years. This is to ensure their diagnoses and treatments are based on the latest discoveries.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

Diacomit Add-On Therapy More Effective in Children with Dravet Syndrome Who Carry Pathogenic SCN1A Mutations, Study Shows

Diacomit (stiripentol) add-on therapy is more effective in children with Dravet syndrome who have pathogenic (disease-causing) SCN1A mutations than in those with variants of unknown significance and benign SCN1A mutations, a study has found.

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GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for EPIDIOLEX® (Cannabidiol) Oral Solution CV in Patients with Dravet Syndrome

GW Pharmaceuticals announces positive top-line results of the second randomized, double-blind, placebo-controlled Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the treatment of seizures associated with Dravet syndrome, a rare and severe form of childhood-onset epilepsy.

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Aquestive Therapeutics Announces FDA Approval for SYMPAZAN™ (clobazam) Oral Film

The FDA approved SYMPAZAN™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. SYMPAZAN is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

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Diagnostic Advances

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases showing nearly a third of children had a change in diagnosis based on new data.

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Research Discoveries

Could Lab-Grown Human Minibrains Help Treat Alzheimer’s and Epilepsy?

Featuring the work of CURE Grantee Dr. Steven Petrou

Florey Institute Director Dr. Steven Petrou leads research creating organoids to mimic the behavior of children’s brains with rare, debilitating forms of epilepsy. Replicating the way neurons behave in children with epilepsy using stem cells in a dish allowed the researchers to tailor a treatment; Petrou is on the verge of announcing a clinical trial of a gene therapy to treat one variant of the disorder.

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Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring the work of CURE Grantee Dr. Harald Sontheimer

A research team led by Dr. Harald Sontheimer determined that perineuronal nets, whose function was previously unknown, modulate electrical impulses in the brain. Seizures can occur if the nets are dissolved. This discovery may lead to a potential treatment for acquired epilepsy.

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Epidemiology of Status Epilepticus in Adults: A Population-Based Study on Incidence, Causes, and Outcomes

The first population-based study using the International League Against Epilepsy 2015 definition and classification of status epilepticus found an increase of incidence of 10% compared to previous definitions. The study also provides epidemiologic evidence that different patterns of status evolution and level of consciousness have strong prognostic implications.

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Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Scientists at the UNC School of Medicine found evidence that genetic therapy may prevent the enhanced seizure susceptibility common in children with Angelman Syndrome. The research marks the first time scientists reduced seizure susceptibility in mice by activating a dormant copy of the UBE3A gene, so it could replace the faulty mutant version.

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Also Notable

Parents and Researchers Work to Find Cause of Neonatal Epilepsy

Three US families aim to help researchers develop better treatments for neonatal-onset epilepsy with a US-wide study called Early Recognition of Genetic Epilepsy in Neonates (ERGENT). This study provides free-of-charge genetic testing to babies who have features suggestive of a genetically-caused epilepsy.

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Alzheimer’s and Epilepsy: Intimate Connections

Like people with Alzheimer’s disease, people with epilepsy can experience memory loss or confusion. As part of an aura, they may hear or see things that aren’t there. When older adults display these symptoms, they may be misdiagnosed with Alzheimer’s disease, when in fact they are having (or just had) a seizure.

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Genome-Wide Mega-Analysis Identifies 16 Loci and Highlights Diverse Biological Mechanisms in the Common Epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. Researchers report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel.

Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain.

The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

HudsonAlpha Scientists Identify “Poisonous” Piece of Genetic Code Causing Infant Seizures

Featuring the Work of CURE Grantee Gemma L. Carvill, PhD

Researchers at the HudsonAlpha Institute for Biotechnology have pinpointed a previously unknown cause of a serious seizure disorder most common in babies, potentially opening the door to new diagnostic and treatment options for infants that show signs of epilepsy.

They found the genetic cause hidden in the SCN1A gene, one of the most heavily studied genes for seizure disorders. The discovery offers an end to the diagnostic odyssey for affected patients, but it also reveals a genetic mechanism for disease that could uncover the cause of other genetic disorders that are not currently well understood.

Scientists in Greg Cooper’s Lab at HudsonAlpha, along with collaborators from across the country, published their findings in the American Journal of Human Genetics. They identified a variant that cues a poisonous piece of genetic code, called a poison exon, to be included in the final instructions for making a crucial protein. When the poison exon is incorporated, it prematurely cancels the protein’s production, which disrupts neural function leading to seizure disorders.

The lab found the mutation on the SCN1A gene after performing whole genome sequencing for a patient that showed symptoms of a disease called Dravet Syndrome, a serious seizure disorder that most commonly appears in infants. This particular variant would not show up on any of the more common genetic tests and it was only identified because the entire genome was sequenced.

Ben Philpot, PhD

Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Angelman syndrome is a genetic disease with no cure. Children grow up with severe intellectual disabilities and a range of other problems, arguably the worst of which are epileptic seizures. Now scientists at the UNC School of Medicine have found evidence that genetic therapy may prevent the enhanced seizure susceptibility.

Published in the Journal of Clinical Investigation, the research marks the first time scientists were able to reduce seizure susceptibility in mice by activating a dormant copy of the UBE3A gene so it could replace the faulty mutant version. While replacing the faulty gene in juveniles reduced seizures, replacing the faulty gene in adult mice had no effect.

The UNC scientists also found evidence that the loss of this gene in Angelman syndrome promotes seizures by impairing the normal activity of inhibitory neurons – cells that normally keep brain circuits from being overstimulated.

“This result implies that if you want to limit epilepsy in Angelman syndrome, you’ll need at least to restore the function of UBE3A in inhibitory neurons,” Philpot said.

From Molecules to Medicines: the Dawn of Targeted Therapies for Genetic Epilepsies

Precision medicine is the treatment of patients with therapy targeted to their specific pathophysiology. This lofty ideal currently has limited application in clinical practice. However, new technological advances in epilepsy models and genomics suggest that the precision medicine revolution is closer than ever before. We are gaining an improved understanding of the true complexity underlying the pathophysiology of genetic epilepsies and the sources of phenotypic variation that continue to frustrate efforts at genotype–phenotype correlation.

Conventional experimental models of epilepsy, such as mouse models and heterologous expression systems, have provided many of the advances in our understanding of genetic epilepsies, but fail to account for some of these complexities. Novel high-throughput models of epilepsy such as zebrafish and induced pluripotent stems cells can be combined with CRISPR–Cas9 gene editing techniques to explore the pathogenesis of a specific gene change and rapidly screen drug libraries for potential therapeutics.

The knowledge gained from these models must be combined with thorough natural history studies to determine appropriate patient populations for pragmatic clinical trials. Advances in the ‘omics’, genetic epilepsy models and deep-phenotyping techniques have revolutionary translational research potential that can bring precision medicine to the forefront of clinical practice in the coming decade.

UBE3A Gene Reactivation in Inhibitory Neurons May Prevent Seizures, Angelman Mouse Study Shows

Epileptic seizures caused by disturbances in the activity of a specific type of nerve cell called an inhibitory neuron were prevented by the reactivation of the UBE3A gene in young mice with Angelman syndrome features, a study shows.

The study, “Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice,” was published in The Journal of Clinical Investigation.

The disorder is frequently associated with epileptic seizures — estimated to affect between 80% and 95% of patients — that usually fail to respond to anti-epileptic medications. However, the reason why genetic mutations in UBE3A seem to increase patients’ risk of developing epileptic seizures is not yet fully understood.

Although there is no cure for Angelman syndrome, recent studies in mouse models based on UBE3A gene replacement or reactivation in neurons hold great therapeutic potential, including for the treatment of epilepsy.

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases that showed nearly a third of children had a change in diagnosis based on new data.

Based on these data, scientists are calling for parents to review gene tests done in children with epilepsy at least every two years to ensure their diagnoses and treatments are based on the latest discoveries. This finding is significant because the leading genome societies have suggested periodic checks but have not recommended how frequently these should be made.

Much remains unknown about the human genome. One widely used database contains about 175,000 “variants of uncertain significance” – approximately double the number of genetic variants believed to cause disease.

Still, the new research shows how quickly scientists are piecing the puzzle together. The study found that 31 percent of the patients received a diagnosis based on a new understanding of their genetic variant within the five-year window. In patients who received a genetic test result as recently as two years prior, researchers still found 25 percent had a disease-causing variant reclassified.

New Causative Gene Found in Severe Childhood Epilepsy

A large international research team has discovered a new genetic cause for a severe, difficult-to-treat childhood epilepsy syndrome. Spontaneous mutations in one gene disrupt the flow of calcium in brain cells, resulting in epileptic overactivity. The team’s research in patients also found clues to potential medical treatments for the rare condition.

“Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene’s associated protein affect brain function–causing neural overactivity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia (CHOP). “Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients.”

The research team focused on disease-causing changes in the CACNAIE gene, long suspected to play a key role in how neurons regulate their electrical activity, but not previously known to cause human disease. This study was the first to link the gene to human epilepsy.