Researchers discover eight new epilepsy genes

November 6, 2017, University of Montreal
Generalized 3 Hz spike and wave discharges in a child with childhood absence epilepsy. Credit: Wikipedia.

Approximately 30 per cent of patients with epilepsy do not respond to anti-epileptic drugs. In these cases, all neurologists can do is attempt to find the right combination of medication through trial and error. A treatment that could target the root cause of epilepsy is a beacon of hope for these patients. But identifying the cause of the pathology is no easy feat. "There are many genes involved," said Jacques Michaud, pediatrician at CHU Sainte-Justine and Professor of Pediatrics and Neuroscience at the Faculty of Medicine of Université de Montreal. "Each child can have different genetic mutations. Often the clinical symptoms do not clearly reflect the cause of epilepsy, which makes choosing the right treatment more difficult."

A recent study by Michaud examining 200 children with epileptic encephalopathy - combined with intellectual or overall developmental disability - and their parents could lead to the development of a more rational anti-epileptic treatment strategy. This extensive research project was piloted by Michaud and his colleagues, Elsa Rossignol and Patrick Cossette of Universite de Montréal and Berge Minassian of the University of Toronto. The team identified eight new genes involved in this type of epilepsy thanks to their use of whole-genome sequencing, which had never been done before in an epileptic study of this scope. The results of their study were recently published in the American Journal of Human Genetics. "By learning about the pathophysiology of the genes involved, we hope to move towards a more appropriate treatment and decrease the amount of time spent on cumbersome medical assessments," said Michaud.

This discovery has had further-reaching implications. The findings not only validate the systematic approach to whole-genome sequencing in clinics, they also demonstrate that de novo mutations, otherwise known as not inherited by parents, are the main cause of this severe type of epilepsy. "We were able to identify the specific genetic change that led to epileptic encephalopathy in 32 per cent of our subjects, which is quite remarkable," said Michaud.

"These children underwent extensive medical assessments, but no one could find the main cause. If we had conducted this analysis earlier, before all the medical tests were performed, it is possible the yield would have been even greater."

A collective effort on an international scale

Michaud, who holds the Jeanne and Jean-Louis Lévesque Research Chair on the genetic basis of brain diseases and the Jonathan Bouchard Research Chair on intellectual disability, believes that using whole-genome sequencing in a clinical setting has added value compared to the more conventional approach based on the exome, which represents less than 2 per cent of the genome. "Thanks to whole-genome sequencing, we were able to identify a larger number of mutations," he said. "In the future, the development of new methods for analyzing data will make it possible to improve diagnostic performance."

This scientific breakthrough was made possible thanks to the collective efforts of more than 100 researchers from around the world. "We developed a network of collaborators in the United Kingdom, in several other European countries and in Australia to identify 30 other children with mutations in the same ," said Michaud. "This is how we were able to validate our findings."

In the context of epilepsy, he added, de novo mutations seem to involve mechanisms of gene disruption that are unlike those involved in intellectual disability. "Mutations in epilepsy tend to affect specific areas of the gene, whereas mutations associated with intellectual disability are more often distributed throughout the entire gene. This pattern suggests that mutations in epilepsy impart specific properties to their corresponding proteins, which may then manifest as a decrease or increase in protein activity. In , will simply deactivate the gene."

Knowledge of these mechanisms of action is crucial for the development of personalized epilepsy treatments. However, much more work is needed before these treatments can be harmonized with patients' genetic profiles.

Explore further: Intellectual disability is frequently caused by non-hereditary genetic problems

More information: Fadi F. Hamdan et al, High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.09.008

Related Stories

Intellectual disability is frequently caused by non-hereditary genetic problems

April 18, 2011
Mutations in a group of genes associated with brain activity frequently cause intellectual disability, according to a study led by scientists affiliated with the University of Montreal and the research centre at the Centre ...

Epileptic encephalopathy linked to protein trafficking gene

November 28, 2016
Researchers have linked a debilitating neurological disease in children to mutations in a gene that regulates neuronal development through control of protein movement within neuronal cells.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Exome sequencing: Potential diagnostic assay for unexplained intellectual disability

November 8, 2012
Research findings confirming that de novo mutations represent a major cause of previously unexplained intellectual disability were presented on Nov. 8 at the American Society of Human Genetics 2012 meeting in San Francisco.

A new molecular mechanism related to epilepsy and intellectual disability

May 15, 2017
Epilepsy and intellectual disability, which usually have their onset during childhood, are in some cases linked to mutations in the gene KIAA1202, which contains the information to produce the protein Shrm4. An international ...

Intellectual disabilities caused by protein defect

September 4, 2017
Intellectual disabilities are often caused by a mutation that damages a gene, preventing the associated protein from functioning properly. However, a mutation can also change the function of a gene. As a result, the gene ...

Recommended for you

New software helps detect adaptive genetic mutations

February 20, 2018
Researchers from Brown University have developed a new method for sifting through genomic data in search of genetic variants that have helped populations adapt to their environments. The technique, dubbed SWIF(r), could be ...

15 new genes identified that shape human faces

February 20, 2018
Researchers from KU Leuven (Belgium) and the universities of Pittsburgh, Stanford, and Penn State have identified 15 genes that determine facial features. The findings were published in Nature Genetics.

Highly mutated protein in skin cancer plays central role in skin cell renewal

February 20, 2018
Approximately once a month, our skin completely renews itself. If this highly coordinated process goes awry, it can lead to a variety of skin diseases, ranging from skin cancer to psoriasis. Cells lining such organs as skin ...

New algorithm can pinpoint mutations favored by natural selection in large sections of the human genome

February 20, 2018
A team of scientists has developed an algorithm that can accurately pinpoint, in large regions of the human genome, mutations favored by natural selection. The finding provides deeper insight into how evolution works, and ...

Study of smoking and genetics illuminates complexities of blood pressure

February 15, 2018
Analyzing the genetics and smoking habits of more than half a million people has shed new light on the complexities of controlling blood pressure, according to a study led by researchers at Washington University School of ...

New mutation linked to ovarian cancer can be passed down through dad

February 15, 2018
A newly identified mutation, passed down through the X-chromosome, is linked to earlier onset of ovarian cancer in women and prostate cancer in father and sons. Kunle Odunsi, Kevin H. Eng and colleagues at Roswell Park Comprehensive ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.