Researchers have discovered 11 genetic variants linked to rare childhood epilepsies by comparing genomic with phenotypic data.
This study, which was published in the American Journal of Human Genetics, builds on previous work by the same team at the Children’s Hospital of Philadelphia also researching the genetics behind epilepsy in childhood.
These early and rare forms of epilepsy can be difficult to treat and have more than 100 known genetic causes. Matching symptoms with genetic variants and accurately predicting outcomes for patients can be a challenging process.
In this study, the team, led by Ingo Helbig, MD, a physician at the Children’s Hospital and researcher at the University of Pennsylvania, carried out a computer analysis comparing exome sequencing data from 846 children with epilepsy, who had undergone genomic sequencing as part of previous studies, with phenotypic symptom data from the same individuals.
As in previous studies, the researchers used terms from the Human Phenotype Ontology database to describe over 30,000 symptoms and ensure consistency between participants and descriptions from different physicians.
The researchers looked for abnormal variation in genes that could be a cause for the epilepsy symptoms the participants experienced. They isolated 41 gene variants that were all present in at least two people in the cohort and on further analysis showed that 11 associations between genetic variants and phenotypes were statistically significant.
Changes in the gene SCN1A have previously been linked to childhood epilepsies and in this study the researchers found significant links between variants in this gene and ‘complex febrile seizures’ and ‘focal clonic seizures’.
Similarly, variants in the gene STXBP1 have previously been linked to infantile and epileptic spasms in babies and in this study the team also found a significant association between changes in this gene and ‘absent speech’. They also found a link between variation in the SLC6A1 gene and ‘EEG with generalized slow activity’
“Traditionally, many of the genetic epilepsies that we now develop treatments for were described because of a specific set of clinical features that stood out. However, this type of traditional description of new diseases requires patients to be seen by the same provider or within the same center. What we have done with this study is re-engineered the cognitive process that goes on when clinicians discover a new syndrome,” Helbig said.
“We have developed a computational mechanism to replicate this type of discovery from large, de-identified clinical data. As the amount of deep phenotypic data available to us increases, we now have the ability to identify novel genetic causes of particularly severe forms of epilepsy that are targets for new treatments.”
