A recent study with significant participation by Kiel University (CAU) shows which genetic mutations cause developmental disorders and epilepsy. The results could significantly improve the current genetic tests. In addition, the international research team led by Professor Ingo Helbig, which includes the Kiel working group on epilepsy genetics at the Department of Pediatric and Adolescent Medicine II (Director: Professor Ulrich Stephani) at the University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, showed that a large number of patients can benefit from such improved tests, because they enable targeted successful treatments to be developed. The study was recently published in the prestigious scientific journal „Nature Genetics“.
In the meta study, scientists analysed a globally-unique high number of cases. This was made possible through the close cooperation of many international partners, including researchers from Kiel, Antwerp, Boston, London and Tübingen. The researchers analysed the data from 6,753 trios: children with various neurodevelopmental disorders (NDDs) as well as their healthy mothers and fathers. 1,942 of these children were also diagnosed with epilepsy. With these parent-child trios, almost the entire genome was investigated, approximately 22,000 genes. The researchers were looking for mutations in the genetic material, with the simultaneous occurrence of developmental disorders and epilepsy. They found corresponding point mutations very frequently in 33 genes, and could thus identify them as important genes for epilepsy.
The most important finding in the investigation is a list of 33 genes which are associated with the development of epilepsy symptoms. A large number of these genes were previously unknown in this context. With the help of the list, genetic diagnostics in children with developmental disorders and epilepsy can be substantially improved, emphasised Professor Johannes Lemke from the participating Clinic for Human Genetics at the University of Leipzig Medical Center: „The list is a first step towards a recommendation on which genes should be selected for epilepsy genetic tests in the future. Therefore our research findings have great potential to improve diagnostic results.“
The current work is based on the joint analysis of large data sets, which have been built up over the years by various research projects. The Kiel epilepsy genetics working group led by Professor Ingo Helbig played a major role in the data preparation and analysis. They have been researching predisposition factors for epilepsies for over ten years. Their methodological focus is on high-throughput sequencing, and in particular trio-exome sequencing (investigating the child and both parents). „Medicine is becoming increasingly digital. Our current study shows how we can increasingly derive new knowledge from the joint analysis of large data sets. It is also becoming clear how important it is that we are a leader in the application of modern IT techniques – especially for rare paediatric neurological diseases. We create diagnoses for our patients, which enable targeted treatment,“ said Helbig on the new diagnostic possibilities.
Epilepsy is an extremely diverse disease. Particularly where there is an additional developmental disorder, there are often underlying genetic causes, continued Helbig. „Genetic tests are therefore an important diagnostic tool. But at the moment, each test provider selects which genes will be investigated, according to their own criteria. This means that the tests are not standardised. The relevance of their findings can therefore vary greatly. To date, there are no guidelines regarding which epilepsy genes should be investigated in such tests. Each provider thus determines the design of the so-called gene panels themselves. In our study we were able to show that each of the panels currently offered only covers around half of the relevant genes,“ added Lemke.
The method is ideally suited to identifying causes of epilepsies, confirmed private lecturer Hiltrud Muhle, senior physician at the Department of Pediatric and Adolescent Medicine II at the UKSH Campus Kiel, and director of the Kiel Social Paediatric Centre (SPZ, Sozialpädiatrische Zentrum): „The genes identified now should always be included in relevant gene panel sequencing. Sooner or later, trio-exome testing should be used diagnostically earlier and more broadly,“ suggested the physician. „A significant proportion of epilepsies can be identified using this method, especially in cases of early onset, and with combinations of epilepsy and developmental disorders. This helps avoid unnecessary time-consuming investigations, and individual treatment concepts can be developed at an early stage.“
„It is often claimed that genetic diagnoses hardly influence the treatment of children with mental disability, autism or epilepsy. In our study, we prove the opposite. If a genetic cause can be found for the developmental disorder with epilepsy, one in four children can get a better individual treatment recommendation,“ according to Lemke. Many of the genes identified by the study affect ion channels in the brain. These determine how well or badly the stimulus conduction of the nerves functions. If the flow is disturbed, it can lead to seizures. “If a paediatrician is made aware of such an ion channel disease through a test, they can prescribe medication specifically to improve the ion flow in the nerve cells,“ explained the study leader. He is therefore certain that the results of the study will provide much material for further discussion, after publication in „Nature Genetics“: „Not only among physicians, but also among health insurers, because genetic testing plays an ever-greater role in treatment decisions.“
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contact for scientific information:
Prof. Dr med. Johannes Lemke
Clinic for Human Genetics at the University of Leipzig Medical Center
Tel.: +49 341 97-23800
Dr Henrike Heyne is the study’s lead author:
“De novo variants in neurodevelopmental disorders with epilepsy”, https://www.nature.com/articles/s41588-018-0143-7, in Nature Genetics, doi: 10.1038/s41588-018-0143-7