Prof Sam Berkovic: a “major advance” in the genetic basis of epilepsy


By Mardi Chapman

8 Aug 2019

Prof Sam Berkovic

Australian neurologists have played a leading role in research that is slowly teasing out the complex patterns of inheritance of common and ultra-rare genetic risk variants in epilepsy.

Using whole-exome sequencing, the Epi25 Collaborative study compared more than 9,000 people with epilepsy and 8,400 controls from 37 sites worldwide including Austin Health, Melbourne.

It focused on people with severe developmental and epileptic encephalopathies (DEEs), genetic generalised epilepsy (GGE), non-acquired focal epilepsy (NAFE) and other epilepsy syndromes.

People with epilepsy, except for those with NAFE, carried a significant excess of ultra-rare protein-truncating variants (PTVs) and damaging missense variants compared to controls.

And the PTVs were enriched in candidate epilepsy-associated genes for individuals with DEEs relative to other epilepsy subgroups.

“Although no single gene surpassed exome-wide statistical significance to be associated with GGE or NAFE, specific gene sets that had previously been associated with epilepsy or with encoding biologically interesting entities showed a clear enrichment of deleterious URVs,” the study authors said.

“Specifically, we observed a significant excess of deleterious URVs in constrained genes, established epilepsy-associated genes, and GABAA receptor subunit genes, a larger group of genes delineating the GABAergic pathway, and also in all cation-channel-encoding genes.”

They said the results support the concept that defects in GABAergic inhibition underlie various forms of epilepsy.

Professor Sam Berkovic, director of the Epilepsy Research Centre at Austin Health and an investigator in Epi25, told the limbic the findings don’t have an immediate clinical impact but opened the door to better understanding the genetic basis of the common epilepsies.

“One of the bigger mysteries for me has been that GGE has been known to have a major genetic component to it. Twins usually both get it, it runs in families although not like a true dominant disorder, it is highly heritable but finding the genetic basis of that has been really elusive. It’s clearly going to have many layers but now we are starting to uncover that.”

“This is the first really good go at finding what might underlie why it runs in families and once we understand that we will be able to counsel people much more accurately about the likelihood of their next child having it, etc.”

“I’m hoping this work will enter the diagnostic realm in the next few years and that new therapies based on this will then be a few years after that. But it really is a major advance compared to where we were a few years ago when the genetic basis of epilepsy was a real mystery.”

He said the work represents the first two years of data from a five-year project and that numbers of participants would grow from the current 9,000 to over 25,000.

“I’m hoping that as the sample size grows, the discovery will increase exponentially and I think that is a reasonable expectation.”

“At a fundamental level of practice, genetics is very important particularly for the childhood epilepsies and that is making a big difference. For the commoner sorts of epilepsies, I don’t want to overstate the clinical importance but I think that is now just around the corner.”

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