Royal College of Surgeons in Ireland
The_Epilepsy_Genetics_Initiative_Systematic_reanalysis_of_diagnostic_exomes_increases_yield.pdf (189.83 kB)

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

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journal contribution
posted on 2021-04-15, 16:37 authored by Samuel F Berkovic, David B Goldstein, Erin L Heinzen, Brandon L Laughlin, Daniel H Lowenstein, Laura Lubbers, Randall Stewart, Vicky Whittemore, Kaitlin Angione, Carl W Bazil, Louise Bier, Judith Bluvstein, Elise Brimble, Colleen Campbell, Gianpiero CavalleriGianpiero Cavalleri, Chelsea Chambers, Hyunmi Choi, Maria Roberta Cilio, Michael Ciliberto, Susannah Cornes, Norman DelantyNorman Delanty, Scott Demarest, Orrin Devinsky, Dennis Dlugos, Holly Dubbs, Patricia Dugan, Michelle E Ernst, Melissa Gibbons, Howard P Goodkin, Ingo Helbig, Laura Jansen, Kaleas Johnson, Charuta Joshi, Natalie C Lippa, Eric Marsh, Alejandro Martinez, John Millichap, Maureen S Mulhern, Adam Numis, Kristen Park, Tommaso Pippucci, Annapurna Poduri, Brenda Porter, Brigid Regan, Tristan T Sands, Ingrid E Scheffer, John M Schreiber, Beth Sheidley, Nilika Singhal, Lacey Smith, Joseph Sullivan, Alan Taylor, Patricia Tolete, Tahseen M Afgani, Vimla Aggarwal, Rosemary Burgess, Tracy Dixon-Salazar, Parisa Hemati, Julie Milder, Slavé Petrovski, Anya Revah-Politi, Nicholas Stong

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.


Citizens United for Research in Epilepsy, Grant/Award Number: 339143

National Institute for Neurological Disease and Stroke, Grant/Award Number: U01- NS077303-04S1

The John and Barbara Vogelstein Foundation



The original article is available at

Published Citation

Epilepsy Genetics Initiative. The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield. Epilepsia. 2019;60(5):797-806.

Publication Date

5 April 2019

PubMed ID



  • Beaumont Hospital
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders




  • Published Version (Version of Record)