The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

• Published in: Epilepsia (Copenhagen) Vol. 60; no. 5; pp. 797 - 806
• Main Authors: Berkovic, Samuel F., Goldstein, David B., Heinzen, Erin L., Laughlin, Brandon L., Lowenstein, Daniel H., Lubbers, Laura, Stewart, Randall, Whittemore, Vicky, Angione, Kaitlin, Bazil, Carl W., Bier, Louise, Bluvstein, Judith, Brimble, Elise, Campbell, Colleen, Cavalleri, Gianpiero, Chambers, Chelsea, Choi, Hyunmi, Cilio, Maria Roberta, Ciliberto, Michael, Cornes, Susannah, Delanty, Norman, Demarest, Scott, Devinsky, Orrin, Dlugos, Dennis, Dubbs, Holly, Dugan, Patricia, Ernst, Michelle E., Gibbons, Melissa, Goodkin, Howard P., Helbig, Ingo, Jansen, Laura, Johnson, Kaleas, Joshi, Charuta, Lippa, Natalie C., Marsh, Eric, Martinez, Alejandro, Millichap, John, Mulhern, Maureen S., Numis, Adam, Park, Kristen, Pippucci, Tommaso, Poduri, Annapurna, Porter, Brenda, Regan, Brigid, Sands, Tristan T., Scheffer, Ingrid E., Schreiber, John M., Sheidley, Beth, Singhal, Nilika, Smith, Lacey, Sullivan, Joseph, Taylor, Alan, Tolete, Patricia, Afgani, Tahseen M., Aggarwal, Vimla, Burgess, Rosemary, Dixon‐Salazar, Tracy, Hemati, Parisa, Milder, Julie, Petrovski, Slavé, Revah‐Politi, Anya, Stong, Nicholas
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2019; John Wiley and Sons Inc
• Subjects: Adolescent; Adult; Child; Child, Preschool; data sharing; Databases, Genetic; Delayed Diagnosis; Diagnosis; Epilepsy; Epilepsy - diagnosis; Epilepsy - ethnology; Epilepsy - genetics; Exome; Exome Sequencing; Family Health; Female; Full‐length Original Research; Genetic screening; Humans; Infant; Information Dissemination; Male; Mutation; Parents; Pathogenicity; Retrospective Studies; seizures; Siblings; whole exome sequencing; Young Adult; seizures; data sharing; whole exome sequencing
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.14698

Summary
Objective
The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research‐based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception.
Methods
One hundred sixty‐six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis.
Results
Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES.
Significance
EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.