The Epilepsy Phenome/Genome Project

Abstract

Background Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. Results EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. Conclusions EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

De novo KCNB1 mutations in epileptic encephalopathy

“…Individual 3 (Coriell ND27062) was ascertained by the Epilepsy Phenome/Genome Project 13 as part of a patient cohort with infantile spasms and/or Lennox-Gastaut syndrome. 5 Seizure onset occurred during the first year of life and seizure types include tonic-clonic, atypical absence, atonic, infantile spasms and focal dyscognitive (Table 4).…”

Sex differences in seizure types and symptoms

“…Participants were identified through a combination of prospective screening of clinic patients, retrospective review of medical records, and education and recruitment of colleagues within the primary EPGP institutions and neighboring institutions. [23] After obtaining informed consent from the subject, all clinical and demographic data were gathered prospectively through semi-structured interviews as well as review of medical records, EEG, and imaging data. Figure 1 depicts the data collection and review processes and the three points at which eligibility was re-assessed following obtaining informed consent.…”

“…If the EEG was normal, there had to be clear clinical history and the data were sent for review and adjudication. [23] For NAFE, subjects had neuroimaging which was either normal or demonstrated mesial temporal sclerosis or focal cortical dysplasia and an unambiguous clinical semiology consistent with focal seizures and/or focal EEG abnormalities. Patients with benign rolandic epilepsy based upon clinical presentation were not required to have neuroimaging.…”

“…[23] The interview was modified from a previously validated instrument. [25, 26] When necessary, data were reviewed and adjudicated by the Phenotype Core.…”

“…Systematic quality reviews were conducted to identify and correct errors in phenotypic data[23]. All data were stored electronically in a central repository[27].…”