Scientists discover rare genetic variants associated with epilepsy in large-scale study

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For the first time, scientists have mapped out the genes associated with epilepsy. The study is one of the largest of its kind to look into the genetic make-up of people with epilepsy. The research, which was conducted by scientists from Austin Health and the University of Melbourne was published in the latest issue of the journal American Journal of Human Genetics.

DNA with rare genetic variant highlightedBlue Andy | Shutterstock

The team of researchers included patients from different nations and included around 18000 persons. Rare genetic variants within these patients pointed at their association with epilepsy. The team writes that there have been genetic sequencing studies before that have noted genetic association with severe epilepsies.

Even certain gene deletions have been found to be associated with less severe forms of epilepsy. This study looked at the “ultra-rare genetic risk factors for different types of epilepsies,” they wrote.

Epilepsy affects 5 to 7 individuals among every 1000 in the global population and this sheer number prompted them to find the underlying genetic risk factors for the disease.

Professor Sam Berkovic, Director of Epilepsy with Austin Health and Laureate Professor with the University of Melbourne explained that severe forms of epilepsy seemed to have a genetic basis and this study shows that even less severe forms of epilepsy carried an association with genes.

There are approximately 50 million people across the world with epilepsy, a condition that causes repeated seizures due to excessive electrical activity in the brain. Epilepsy comes in a number of different forms ranging from less common variations such as developmental and epileptic encephalopathies that cause severe symptoms, to other, less severe forms such as genetic generalised epilepsy and non-acquired focal epilepsy that account for up to 40 per cent of cases.”

Professor Sam Berkovic, University of Melbourne

He added, “This research is important because the more we understand the genes that are linked to epilepsy, the better we can tailor treatments to reduce the symptoms and let patients live more active lives.”

This was a collaborative effort of over 200 researchers, explained the leading team. A total of 17,606 people provided their genetic data from 37 different sites across Europe, Australia, Asia, and North America.

The team included 9,170 epilepsy-affected individuals compared with 8,436 controls with European ancestry. Both severe and less severe forms of epilepsy were included in the analysis, explained the team.

Three types were noted among the patients, “severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE).”

The genetic sequencing part of the study was performed at the Broad Institute, Boston, led by Dr Benjamin Neale. Melbourne was the center where the data was collated and analyzed finally they explained. From Austin Health and the University of Melbourne alone 1370 patients were included in the study.

The team defined each of the conditions stating –

  • “Diagnosis of GGE required a convincing history of generalized seizure types (generalized tonic-clonic, absence, or myoclonic seizures) and generalized epileptiform discharges on EEG”
  • “Diagnosis of NAFE required a convincing history of focal seizures; an EEG with focal epileptiform or normal findings (since routine EEGs are often normal in focal epilepsy).”
  • “DEE group was comprised of subjects with severe refractory epilepsy of unknown etiology, with developmental plateau or regression, with no epileptogenic lesion on MRI, and with epileptiform features found on EEG.”

The strongest association was noted with genetic deletions and variants with DEE and least strong association was noted with NAFE. In all three classes of epilepsy, the team found that there was a genetic defect in the genes encoding for the GABAA receptors.

In DEEs and GGEs, there was a higher risk of these defects, they wrote. The team writes that the lead genetic viriants seen with the different types of epilepsy were, “CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE.”

Genetic sequencing has significantly improved our understanding of the risk factors association with epilepsy in recent years. This study shows that more and less severe forms of the disease share similar genetic features, and the more we understand these features the better chance we have to personalise the care we give to patients.”

Professor Sam Berkovic, University of Melbourne

He explained, “There are already plans in place to double the size of the study in the next year to further explore the significance of the genetic variations that are linked with epilepsy.”

Journal reference:

Epi25 Collaborative. (2019). Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals.

Dr. Ananya Mandal

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.


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