Epi4K consortium.; Epilepsy Phenome/Genome Project.. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017 Feb;16(2):135-143.
Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies.
We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies.
We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes.
We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future.
Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.
In recent years, researchers have identified dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy…
The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.
For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center…
The findings have important implications for clinical practice and for research. “At present, all common epilepsies are treated the same way, with the same group of medications,” said Dr. Goldstein. “But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype.”
“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”