Ingo Helbig, MD – The Children’s Hospital of Philadelphia
Ethan M. Goldberg, MD, PhD – The Children’s Hospital of Philadelphia
Generating a shareable clinico-genomic data resource for Dravet syndrome
2023 Genetic RFA – $1,000,000, 3 years
Individuals with Dravet syndrome can have different disease courses, and there are important differences in how seizure and development differences affect them over time. For example, some individuals have longer periods of seizure freedom, while other individuals have frequent seizures. Some individuals with Dravet syndrome have severe developmental differences and autism, while other individuals have typical or near-typical development. Even though the reasons for these differences have been discussed in the research field for the last decades, the underlying causes are not known. Identifying these causes may be helpful in providing accurate prognosis and developing new treatments by understanding the mechanisms. For many conditions, additional genetic factors are known to “modify” the main condition. Accordingly, it is reasonable to suspect the same role of “genetic modifiers” in Dravet syndrome, hopefully explaining some of the differences we see in individuals with Dravet syndrome. For this grant, we have tried to understand what would make a genomic dataset in Dravet Syndrome particularly meaningful. We suggest generating broad genetic data with whole genome sequencing (WGS) on 500 individuals with Dravet syndrome rather than limited genetic data. This is important, as all types of genetic analyses can be performed on this dataset. These genetic analyses will be paired with clinical data. Our advantage is that we have pioneered novel methods on how clinical information can be transformed to a format that can be used for computational analysis. Finally, we want to build this project for data sharing – all biosample data, genomic data, and clinical data will be shared within the Dravet Syndrome Community.
We have three aims for our project. First, we will use the infrastructure of our DSF-recognized Dravet Syndrome Comprehensive Care Center to enroll 500 individuals with Dravet syndrome in our research protocol. We will also gather information from 50 deceased individuals where DNA samples are available, either from research studies or diagnostic labs. We will translate the clinical data into a de-identified format for data sharing and analysis. Finally, we will use the so-called CAVATICA platform for data sharing, a tool that is supported by the NIH for data sharing. Our second aim is to use this dataset of genomic and clinical information to assess how different types of genetic variation on 25 clinical features that we derive from the medical records. This analysis will answer the question of how different types of genetic changes affect outcomes, such as seizure frequency or developmental milestones. As our third aim, we aim to build a clinic where we can share research data with our study participants, but also obtain additional clinical information that will add to our growing research dataset. In summary, we suggest a three-year research project to build a dataset for Dravet syndrome that consists of whole genome data and clinical data. This dataset will make it possible to ask questions on how genomic factors influence Dravet syndrome, which can identify strategies for improved treatment. We will take advantage of recent developments in data privacy to make sure that data sharing is meaningful, but also safe.
About the Investigators:
Ingo Helbig is a pediatrician and child neurologist currently working at the Children’s Hospital of Philadelphia with a focus on the diagnosis and treatment of genetic epilepsies. Dr. Helbig received his clinical and research training at the Epilepsy Research Centre, Melbourne, Australia, the Department of Neuropediatrics at the University of Kiel, and the Division of Neurology, Children’s Hospital of Philadelphia. He has been involved in the discovery of microdeletions as genetic risk factors for epilepsy and has recently co-chaired the European EuroEPINOMICS-RES consortium, a European collaboration involved in many of the recent gene findings for severe epilepsies. He is currently member of the Genetics Commission of the International League Against Epilepsy and member of the ClinGen pediatric neurology clinical domain working group. Ingo is writing about epilepsy and genes on Beyond the Ion Channel, a scientific blog dedicated to epilepsy and genes.
Ethan Goldberg is Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine. He is an Attending Physician and Director of the Epilepsy NeuroGenetics Initiative (ENGIN) at CHOP where he specializes in the diagnosis and care of children with complex
neurological disorders including epilepsy, developmental delay/intellectual disability, and autism spectrum disorder. His biomedical research lab studies basic mechanisms of childhood epilepsy and other neurodevelopmental disorders, with a particular interest in ion channelopathies and how genetic variation in ion channel genes leads to human disease. His lab uses a range of approaches including:
human and mouse genetics; ion channel, cellular and synaptic neurophysiology; pharmacology; induced pluripotent stem cell technology and cell-based therapy; behavior; and imaging approaches including two-photon microscopy in experimental systems.