The Epilepsy NeuroGenetics Initiative (ENGIN) is leading the way toward the discovery of new genetic causes of epilepsy, a better understanding of known genetic epilepsy syndromes, diagnostic testing for more patients and families with epilepsy, and the development of novel treatments for genetic epilepsies.

Children’s Hospital of Philadelphia recognizes the importance of research in this field and what it can do for children with epilepsy and their families. In an effort to continually elevate care for children with epilepsy and other neurogenetic disorders, CHOP has made a significant investment in our Neurogenetics and Epilepsy programs. Our Epilepsy Neurogenetics Initiative was designated a Frontier Program by

Children's Hospital of Philadelphia in 2019. Frontier Programs are unique, cutting-edge programs that will forge important new discoveries, deliver novel therapies, and help even more children thrive.
Through ENGIN, we’re formally integrating genetics into the diagnosis and care of children with epilepsy. ENGIN brings together clinical care and research components that seek to translate research directly into the development of new therapies that will benefit children around the world.

Genetics and genomics

Using genomic sequencing techniques including exome and genome sequencing, we are identifying new genetic causes in children with unexplained epilepsy. ENGIN investigators have been leaders of gene discovery efforts in the epilepsies and have been involved in the identification of more than 30 genetic epilepsy syndromes.

• Whole exome and whole genome sequencing: We are a partner of the Epi25 Collaborative, the largest sequencing effort undertaken to date in the epilepsies. This collaborative aims to deepen our understanding of the genetic causes of epilepsy by sequencing 25,000 individuals with epilepsy.
• Genomic sequencing of surgical specimens: We are analyzing tissue resected from children who have undergone epilepsy surgery to identify somatic mosaic mutations that underlie non-lesional epilepsy that are not otherwise identifiable.
• ClinGen epilepsy gene curation expert panel: ENGIN team members are leaders within the Clinical Genome Resource, which defines the clinical relevance of genes and variants associated with epilepsy, for use in clinical diagnostics, research and precision medicine.

Selected publications

• De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias
  Identified pathogenic variants in voltage-gated calcium channel as new cause of severe epilepsy in infants and children.
• Mutations in SCN3A cause early infantile epileptic encephalopathy
  Study identified pathogenic variants in voltage-gated sodium channel in children with epileptic encephalopathies. This is the first study definitively linking this sodium channel to severe epilepsy in children.  
• De novo variants in neurodevelopmental disorders with epilepsy
• Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood
  New genetic cause of degenerative neurological condition.
• A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy
• The ClinGen epilepsy gene curation expert panel-bridging the divide between clinical domain knowledge and formal gene curation criteria
• Ultra-rare genetic variation in the epilepsies: A whole-exome sequencing study of 17,606 individuals

Basic neuroscience

ENGIN researchers use cellular and advanced model systems to understand how genetic variants affect circuits in the brain and lead to epilepsy. Using animal models, human neurons and organoids (“minibrains”), we are modeling genetic epilepsy syndromes with the goal of developing novel precision treatments.

• Goldberg NeuroLab: Led by principal investigator Ethan Goldberg, MD, PhD, the Goldberg NeuroLab studies the structure and function of cerebral cortical circuits and circuit dysfunction in epilepsy.
  • The lab uses electrophysiology, optogenetics, and two-photon calcium imaging in vivo and in vitro to study normal and epileptic cerebral cortical circuits. Researchers are interested in achieving a greater understanding of mechanisms of epilepsy, using primarily experimental model systems. Research projects focus on:
    • Cellular architecture of epileptic cortical networks
    • Circuit-level mechanisms of epilepsy
    • Treatment/prevention of epilepsy using stem cell-derived cerebral cortical interneuron progenitors
• Channelopathy-Associated Epilepsy Research Center: ENGIN is a site of this multi-institutional and interdisciplinary research center that combines high-throughput technologies on non-neuronal cells with studies of human neuron and animal model systems to understand the consequences of genetic variation in ion channel genes that lead to epilepsy.

Selected publications

• A transient developmental window of fast-spiking interneuron dysfunction in a mouse model of Dravet syndrome
• Alterations of network synchrony after epileptic seizures: An analysis of post-ictal intracranial recordings in pediatric epilepsy patients
• Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome

Clinical and translational research

Our research focuses on better understanding features of known genetic epilepsy syndromes, using advanced data analysis methods to identify optimal treatments, and translating basic neuroscience research into clinical trials and precision therapeutics. Additional research is focused on improving access to genetic services for people with epilepsy and investigating the impact of genetics on health outcomes.

• Deep phenotyping and characterization of genetic epilepsy syndromes
• Use of “big data” from the electronic health record (EHR) to improve care of children with epilepsy: ENGIN scientists use advanced data analysis to extract syndrome-specific information from the electronic medical record to identify optimal treatments and predict complications
• Rett Syndrome Natural History Study: Researchers at CHOP are working to better understand the MECP2 gene mutations that cause Rett syndrome. Our goal is to develop improved treatments to address specific symptoms, and to improve the quality of life for children with this disorder. CHOP is a participating center for the Rett Syndrome, MECP2 Duplication, and Rett-related Disorders Natural History Study. The goal of this study is to gather as much data as possible about children and adults with Rett syndrome in order to stimulate more clinical research and better prepare us for future clinical trials. Learn more about the Rett-related Disorders Natural History Study.
• Precision medicine approaches for genetic epilepsies: ENGIN researchers are pioneers in implementing precision medicine approaches that target the underlying disease mechanisms in genetic epilepsies.
• Clinical trials: We are experts in advanced clinical trial design for rare/ultra-rare disorders.

Selected publications

• A single-center SCN8A-related epilepsy cohort: clinical, genetic, and physiologic characterization
• Targeted treatment of migrating partial seizures of infancy with quinidine
  First study to propose precision treatment for rare genetic epilepsy caused by pathogenic variant in potassium channel. Quinidine — a cardiac medication that blocks this particular potassium channel — was used in a child who became seizure free.
• Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results
• Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial
• Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome
• Treatment responsiveness in KCNT1-related epilepsy