Epilepsy affects 3% of the population and is one of the most common human neurological disorders. With the help of the IGM in collaboration with investigators worldwide, there has been unprecedented success in discovering the genetic basis of epilepsies through existing and developing collaborative efforts (listed below):
Epi4K is an NIH-funded collaborative initiative to identify the genetic bases of the epilepsies by performing genome-wide sequencing of 4,000 individuals with different types of epilepsy. This collaboration led to the identification of three novel epilepsy genes and helped define the genetic architecture of the epilepsies.
Funding: National Institute of Neurological Disorders and Stroke
Epilepsy Phenome/Genome Project Epi4k Consortium. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy. Ann Neurol. 2015, Aug 78(2)323-8.
EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014, Oct 2;95(4):360-70.
Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Galuser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, et al Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature, 2013, Sep 12;501(7466):217-21.
Epi4K Consortium. Epi4K: gene discovery in 4,000 genomes. Epilepsia. 2012, Aug 53(8):1457-67.
The Epi25 project is a partnership between the Broad Institute and the Epi25k Consortium. Epi25k brings together seven large multinational projects, supported by 29 PIs, from locations including Germany, Ireland, Finland, Hong Kong, Japan, Malaysia, US and Australia. Each of these projects maintains a DNA repository amassing over 20,000 cases of the disease. Together, the consortium’s sample collection is the best resource in the world for genetic studies of epilepsy, both in terms of numbers of patients included and the quality of phenotypic information available. We are now focused on global sample collection from various repositories for whole exome sequencing, thus initiating the largest and most ethnically diverse genetic study of epilepsy to date.
Funding: NHGRI Centers for Common Disease Genomics grant.
The EPIGEN consortium was founded in 2005 by David Goldstein, Norman Delanty, Gianpiero Cavalleri, Sanjay Sisodiya, and Chantal Depondt with the central mission of understanding the genetic basis of epilepsy to improve diagnoses and drive the discovery of novel epilepsy therapeutics. The collaboration now has over 10 contributing sites, and over 30 scientists and clinicians actively working on epilepsy genomics. The EPIGEN model is distinct however, in that it is focused entirely on active clinical populations. The enrolled patients in the EPIGEN cohort are primarily cared for by one of the clinical principal investigators at each of the EPIGEN sites, and in this way, the EPIGEN patients benefit from a rich source of continually updated, dynamic clinical information on patients who have a long-standing relationship with their clinician and the multi-disciplinary teams at each site.
Hibar DP, Stein JL, REnteria ME, Arias-Vasquez A, Desrivieres S, Jahanshad N, Toro R, Wittfeld K, Abramovic L, Andersson M, Aribisala BS, Armstrong NJ, Bernard M, Bohlken MM, Boks MP, Bralten J, Brown AA, Chakravarty MM, Chen Q, Ching CR, Cuellar-Partida G, den Braber A, Giddaluru S, Goldman AL, Grimm O, Guadalupe T, Hass J, Woldehawariat G, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kim S, Klein M, Kraemer B, et al Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN, IMAGEN, SYS, Martin NG, Wright MJ, Schumann G, Franke B, Thompson PM, Medland SE. Common genetic variants influence human subcortical brain structures. Nature. 2015, Ap 9;520(7546):224-9.
Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, Ge D, He M, Cirulli ET, Zhao Q, Cronin KD, Gumbs CE, Campbell CR, Hong LK, Maia JM, Shianna KV, McCormack M, Radtke RA, O’Conner GD, Mikati MA, Gallentine WB, Husain AM, Sinha SR, Chinthapalli K, Puranam RS, McNamara JO, Ottman R, Sisodiya SM, Delanty N, Goldstein DB. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet. 2012, Aug 10;91(2)293-302.
Hitomi Y, Heinzel EL, Donatello S, Dahl HH, Damiano JA, McMahon JM, Berkovic SF, Scheffer IE, LEgros B, Rai M, Weckhuysen S, Suis A, De Jonghe P, Pandolfo M, Goldstein DB, Van Bogaert P, Depondt C. Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy.
Ann Neurol. 2013 Sep;74(3):496-501.
Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann O, Bernard M, Brown AA, Cannon DM, Chakravarty MM, Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ, Homuth G, Hottenga JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G, Lee PH, Liu X, Loth E, Lourdusamy A, Mattingsdal M, Mohnke S, et al, Alzeheimer’s Disease Neuroimaging Initiative, EPIGEN Consortium, IMAGEN Consortium, Saguenay Youth Study Group, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium.
Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet. 2012 Ap 15;44(5):552-61.
Kasperaviciute D, Catarino CB, Heinzen EL, Depondt C, Cavalleri GL, Caboclo LO, Tate SK, Jamnadas-Khoda J, Chinthapalli K, Clayton LM, Shianna KV, Radtke RA, Mikati MA, Gallentine WB, Husain AM, Alhusaini S, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Heuser K, Amos L, Ortega M, Zumsteg D, Wieser HG, Steinhoff BJ, Kramer G, Hansen J, Dorn T, Kantanen AM, Gjerstad L, Peuralinna T, Hernandez DG, Eriksson KH, Kalviainen RK, Doherty CP, Wood NW, Pandolfo M, Duncan JS, Sander JW, Delanty N, Goldstein DB, Sisodiya SM. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain. 2010 Jul 133(Pt7):2136-47.
Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute D, Tate SK, Caboclo LO, Sander JW, Clayton L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Kalviainen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Kramer G, Steinhoff BJ, Wieser HG, Zumsteg D, Ortega M, Wood NW, Huxley-Jones J,
Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010 May 14;86(5):707-18.
Epilepsy Genetics Initiative
Given the enormous success of next-generation sequencing in identifying epilepsy-causing mutations, a large number of patients are now being sequenced as part of their clinical care. Although clinical sequencing helps in the genetic diagnosis of several patients, for about 50% of families, such diagnoses remain elusive. Moreover, research from our laboratories and others suggest a complex interplay of factors that sometimes complicates data interpretation. We currently hypothesize that several exome sequencing studies are reported to be negative (i.e. no causal mutation can be identified) not because the underlying cause of the disorder is not genetic, or even because the causal variant lies outside of sequenced regions, but rather simply because the causal variant lies in a gene or region of the genome about which little is known, or has never been reported to be associated with any type of disease. The only way to identify these variants would be to perform the analysis time and time again with the most up-to-date knowledge in hand – a service that is not provided by clinical sequencing entities. The EGI seeks to compile clinical/research generated sequence data from epilepsy patients to oversee systematic and routine analysis and re-analyses of these data to reveal epilepsy risk variants in recently identified epilepsy genes. In addition to providing this important clinical need, the EGI will also use the data to identify novel epilepsy genes, and provide a database of genetic variants to epilepsy researchers to further advance genetic research.
To date, EGI has identified seven variants believed to be causing epilepsy in our patient cohort, representing a diagnosis rate of 4.8% for those participants who did not have a clinical genetic diagnosis at the time of enrollment. Several other genetic variants are being investigated with the potential to result in additional EGI diagnoses.
EGI recently partnered with the Lennox-Gastaut Syndrome (LGS) Foundation who has provided funding for research whole exome sequencing at the IGM for 60+ individuals who have not had access to clinical whole exome testing. The first families have been enrolled, and sequencing is underway. EGI is in the process of establishing similar collaborations with other groups, including the Rare Epilepsy Network (REN), and hope to develop additional partnerships moving forward.
EGI has had a publication accepted by Genetics in Medicine that describes variants in an alternative exon 5 in SCN8A as being causative for epileptic encephalopathy. EGI also contributed a case and was involved in the development of a paper that was recently accepted for publication by the American Journal of Human Genetics implicating the PPP3CA gene and severe neurodevelopmental disease with seizures.
Funding: CURE, National Institute of Neurological Disorders and Stroke
Epilepsy Genetics Initiative (EGI). De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy. Genetics in Medicine. In press.
Myers CT, Stong N, Mountier E, Helbig KL, Freytag S, Sullivan J, Ben Zeev B, Heimer G, Nissenkorn A, Tzadok M, Shinde DN, Rezazadeh A, Reagan B, Oliver K, Ernst ME, Lippa NC, Mulhern MS, Zhong R, Poduri A, Andrade D, Bird LM, Bahlo M, Berkovic SF, Lowenstein D, Scheffer IE, Sadleir LG, Goldstein DB, Mefford HC, Heinzen EL. De novo mutations in PPP3CA cause severe neurodevelopmental disease with seizures. American Journal of Human Genetics. In press.
ILAE Consortium on Genetics of Complex Epilepsies
The ILAE Consortium on Genetics of Complex Epilepsies was formed to advance epilepsy genetics through collaboration. A large focus of the group over several years has been to merge genome-wide genotyping datasets worldwide and perform a centralized analysis looking for epilepsy risk haplotypes across a range of seizure phenotypes.
International League Against Epilepsy Consortium on Complex Epilepsies. firstname.lastname@example.org. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancel Neurol. 2014, Sep; 13(9):893-903.
Pediatric Status Epilepticus Research Group (pSERG)
The pSERG seeks to develop strategies for improving the care and eventually the prognosis of children with status epilepticus. pSERG is also developing a database specific to pediatric status epilepticus to enable better management of present and future patients. The IGM is performing exome sequencing of children who have experienced status epilepticus without any obvious trigger to try to identify genetic risk factors.
Sanchez Fernandez I, Abend NS, Agadi S, AN S, Arya R, Carpenter JL, Chapman KE, Gaillard WD, Glauser TA, Goldstein DB, Goldstein JL, Goodkin HP, Hahn CD, Heinzen EL, Mikati MA, Peariso K, Pestian JP, Ream M, Riviello JJ Jr, Tasker RC, Williams K, Loddenkemper T, Pediatric Status Epilepticus Research Group (pSERG). Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure, 2014 Feb;23(2):87-97.
The Jackson Laboratory (Pediatric epilepsy)
The IGM, in collaboration with the Jackson Laboratory, seeks to develop novel in vitro and in vivo models for severe pediatric epilepsies. Using animal and cell based model systems, neuronal excitability phenotypes in vitro and in vivo will be studied to better understand disease pathophysiology and identify novel therapeutic approaches to treating this devastating epilepsy.
The project focuses on recently identified disease causing variants found in patients with pediatric epileptic encephalopathies, a severe form of epilepsy that occur very early in life and is associated with severe intractable seizures and developmental abnormalities. For analyses, selected disease-causing mutations are mutated in the genome of neuronal cell cultures and screened for electrophysiology phenotypes. The cellular models of epileptic encephalopathies can then be used to study disease pathophysiology and evaluate compounds that might block or reverse the effects of the mutations on the electrical activity of the cell. The same mutations will also be introduced into mice to allow for parallel investigation and study the effects of the mutation in vivo on seizure susceptibility in addition to having model systems to study epileptogenesis.
Funding: National Institutes of Health-1U54OD020351