By Julia Karow
In an effort to unravel the genetics of monogenic forms of epilepsy, a consortium of researchers in Europe has embarked on the Genetics of Rare Epilepsy Syndromes project.
The project proceeds under the umbrella of EuroEpinomics, an epilepsy research program of the European Science Foundation that started in March 2011 and runs for three years.
Funded with more than €3 million from 10 national funding agencies in Europe, the RES project had its kick-off meeting last November and expects to receive exome sequencing data for its first 30 family trios in the near future.
The project involves 10 research groups across Europe and six associated partners and is headed by Peter De Jonghe, a professor at the VIB Department of Molecular Genetics at the University of Antwerp in Belgium, and Ingo Helbig, a professor of molecular and clinical epileptology in the Department of Neuropediatrics at the University Medical Center Schleswig-Holstein in Kiel, Germany.
According to Helbig, epilepsy has been well characterized clinically — better than other neurologic diseases such as autism or schizophrenia — but this is not the case at the genetic level. The first gene involved in epilepsy was discovered in 1994, he said, and about 20 genes for distinct epilepsy syndromes are known today. "There has been quite a lag of translating this very big body of knowledge into genes," he said.
The hope is that a better understanding of the disease mechanisms underlying epilepsy will lead to new therapeutics, as well as to new diagnostics.
Two groups of patients are the focus of the European effort: patients with severe early-onset epilepsy — such as Dravet syndrome or severe myoclonic epilepsy in infancy, or SMEI — where the disease is likely caused by de novo mutations, and large families affected by epilepsy that display Mendelian inheritance patterns.
To study severe early-onset epilepsy, the researchers are sequencing the exomes of patients and their parents. "The hypothesis is that we should find a variant that is not present in the parents but arises de novo in the patient and is actually the cause of the disease," De Jonghe told CSN.
So far, the researchers have about 150 clinically well-characterized patients with early-onset epilepsy and their parents in a database, with the goal to collect about 500 trios.
The first batch of trio exomes is currently being sequenced by the Wellcome Trust Sanger Institute, a partner in the project, using Agilent exome capture technology and sequencing on the Illumina HiSeq 2000. Sanger has developed an algorithm to detect de novo variants, according to De Jonghe, which will be used for the data analysis. Sanger is expected to deliver data within the next few weeks for the first 30 trios, which consortium members will further analyze.
Scientists at the University of Antwerp are also currently testing several exome enrichment kits in conjunction with sequencing on the Life Tech SOLiD 5500xl for sequencing more trios in the future.
For the Mendelian disease project, the researchers have collected about 50 epilepsy families with dominant or recessive inheritance patterns. They plan to sequence the exomes or genomes of one or two patients for each family and look for the segregation of mutations.
Last year, they sequenced the entire genomes of several family members, but "from the financial perspective, the most economic way to go is exomes at the moment," complemented by studies of copy number variants, de Jonghe said.
In addition to trios and families, the researchers have a large number of epilepsy cases available to validate rare mutations they find by targeted next-gen sequencing.
There will be immediate diagnostic benefits to discovering new epilepsy genes, De Jonghe said, for example to counsel families about the recurrence risk of the disease, and to rule out non-genetic causes, such as trauma or infection.
The hope is also to stratify groups of patients by molecular defects in order to have homogeneous cohorts for pharmacological studies, he said.
Genetic testing has already revolutionized the field of epilepsy, Helbig added, allowing doctors in some cases, for example Dravet syndrome, to avoid medications with life-threatening side effects or unnecessary diagnostic testing.
In the long run, De Jonghe said, the researchers also hope to identify targets for the development of new classes of antiepileptic drugs. Given that existing drugs cannot control the disease in about a third of patients, there is a great need for new medications, he added.
The results of the project could further provide new insights into neurodevelopment in general, as well as into neurodegeneration, which is often a feature in complex syndromes where epilepsy is a major syndrome.
The RES project is not the only effort that is banking on next-gen sequencing to discover new epilepsy genes. Last year, for example, the US National Institute of Neurological Disorders and Stroke awarded $25 million over five years to Duke University and others to sequence 4,000 individuals for the so-called Epi4K project (CSN 11/2/2011).
That project will initially sequence the exomes of family trios of patients affected by one of two severe childhood epileptic disorders where de novo mutations are suspected. It also plans to sequence the genomes of multiplex families affected by the disease.
De Jonghe said that the European consortium has no formal collaboration with the Epi4K project but that there are "a lot of contacts" between the two groups.
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