Anne T Berg1,2, Jason Coryell3,4, Russell P Saneto5,6, Zachary M Grinspan7,8,9, John J Alexander10, Mariana Kekis10, Joseph E Sullivan11, Elaine C Wirrell12, Renée A Shellhaas13, John R Mytinger14,15, William D Gaillard16, Eric H Kossoff17,18, Ignacio Valencia19, Kelly G Knupp20,21, Courtney Wusthoff22, Cynthia Keator23, William B Dobyns5,5,24, Nicole Ryan25,26, Tobias Loddenkemper27, Catherine J Chu28, Edward J Novotny5,6,24,29,30,24, Sookyong Koh31. 1. Epilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 2. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 3. Department of Pediatrics, Oregon Health & Science University, Portland. 4. Department of Neurology, Oregon Health & Science University, Portland. 5. Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, Washington. 6. Department of Neurology, University of Washington, Seattle. 7. Department of Pediatrics, Weill Cornell Medicine, New York, New York. 8. Department of Pediatrics, New York Presbyterian Hospital, New York, New York. 9. Health Information Technology Evaluation Collaborative, New York, New York. 10. Department of Human Genetics, Emory University, Atlanta, Georgia. 11. Department of Neurology, University of California, San Francisco. 12. Department of Neurology, Mayo Clinic, Rochester Minnesota. 13. Department of Pediatrics, University of Michigan, Ann Arbor. 14. Department of Pediatrics, The Ohio State University, Columbus. 15. Department of Neurology, Nationwide Children's Hospital, Columbus, Ohio. 16. Department of Neurology, Children's National Health System, George Washington University School of Medicine, Washington, DC. 17. Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland. 18. Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland. 19. Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania. 20. Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora. 21. Department of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora. 22. Division of Child Neurology, Stanford University, Palo Alto, California. 23. Cook Children's Health Care System, Jane and John Justin Neurosciences Center, Fort Worth, Texas. 24. Department of Pediatrics, University of Washington, Seattle. 25. Department of Neurology, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 26. Department of Pediatrics, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 27. Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. 28. Department of Neurology, Massachusetts General Hospital, Boston. 29. Center for Integrative Brain Research, University of Washington, Seattle. 30. Seattle Children's Research Institute, Seattle, Washington. 31. Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
Abstract
Importance: Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established. Objective: To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies. Design, Setting, and Participants: In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined. Exposures: Genetic diagnostic testing. Main Outcomes and Measures: Laboratory-confirmed pathogenic variant. Results: Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%]). Conclusions and Relevance: Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.
Importance: Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established. Objective: To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies. Design, Setting, and Participants: In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined. Exposures: Genetic diagnostic testing. Main Outcomes and Measures: Laboratory-confirmed pathogenic variant. Results: Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%]). Conclusions and Relevance: Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.
Authors: Paul A Harris; Robert Taylor; Robert Thielke; Jonathon Payne; Nathaniel Gonzalez; Jose G Conde Journal: J Biomed Inform Date: 2008-09-30 Impact factor: 6.317
Authors: Johannes R Lemke; Erik Riesch; Tim Scheurenbrand; Max Schubach; Christian Wilhelm; Isabelle Steiner; Jörg Hansen; Carolina Courage; Sabina Gallati; Sarah Bürki; Susi Strozzi; Barbara Goeggel Simonetti; Sebastian Grunt; Maja Steinlin; Michael Alber; Markus Wolff; Thomas Klopstock; Eva C Prott; Rüdiger Lorenz; Christiane Spaich; Sabine Rona; Maya Lakshminarasimhan; Judith Kröll; Thomas Dorn; Günter Krämer; Matthis Synofzik; Felicitas Becker; Yvonne G Weber; Holger Lerche; Detlef Böhm; Saskia Biskup Journal: Epilepsia Date: 2012-05-21 Impact factor: 5.864
Authors: David T Miller; Margaret P Adam; Swaroop Aradhya; Leslie G Biesecker; Arthur R Brothman; Nigel P Carter; Deanna M Church; John A Crolla; Evan E Eichler; Charles J Epstein; W Andrew Faucett; Lars Feuk; Jan M Friedman; Ada Hamosh; Laird Jackson; Erin B Kaminsky; Klaas Kok; Ian D Krantz; Robert M Kuhn; Charles Lee; James M Ostell; Carla Rosenberg; Stephen W Scherer; Nancy B Spinner; Dimitri J Stavropoulos; James H Tepperberg; Erik C Thorland; Joris R Vermeesch; Darrel J Waggoner; Michael S Watson; Christa Lese Martin; David H Ledbetter Journal: Am J Hum Genet Date: 2010-05-14 Impact factor: 11.025
Authors: Monika Maria Eisermann; A DeLaRaillère; G Dellatolas; E Tozzi; R Nabbout; O Dulac; C Chiron Journal: Epilepsy Res Date: 2003 Jun-Jul Impact factor: 3.045
Authors: Andrew S Allen; Samuel F Berkovic; Patrick Cossette; Norman Delanty; Dennis Dlugos; Evan E Eichler; Michael P Epstein; Tracy Glauser; David B Goldstein; Yujun Han; Erin L Heinzen; Yuki Hitomi; Katherine B Howell; Michael R Johnson; Ruben Kuzniecky; Daniel H Lowenstein; Yi-Fan Lu; Maura R Z Madou; Anthony G Marson; Heather C Mefford; Sahar Esmaeeli Nieh; Terence J O'Brien; Ruth Ottman; Slavé Petrovski; Annapurna Poduri; Elizabeth K Ruzzo; Ingrid E Scheffer; Elliott H Sherr; Christopher J Yuskaitis; Bassel Abou-Khalil; Brian K Alldredge; Jocelyn F Bautista; Samuel F Berkovic; Alex Boro; Gregory D Cascino; Damian Consalvo; Patricia Crumrine; Orrin Devinsky; Dennis Dlugos; Michael P Epstein; Miguel Fiol; Nathan B Fountain; Jacqueline French; Daniel Friedman; Eric B Geller; Tracy Glauser; Simon Glynn; Sheryl R Haut; Jean Hayward; Sandra L Helmers; Sucheta Joshi; Andres Kanner; Heidi E Kirsch; Robert C Knowlton; Eric H Kossoff; Rachel Kuperman; Ruben Kuzniecky; Daniel H Lowenstein; Shannon M McGuire; Paul V Motika; Edward J Novotny; Ruth Ottman; Juliann M Paolicchi; Jack M Parent; Kristen Park; Annapurna Poduri; Ingrid E Scheffer; Renée A Shellhaas; Elliott H Sherr; Jerry J Shih; Rani Singh; Joseph Sirven; Michael C Smith; Joseph Sullivan; Liu Lin Thio; Anu Venkat; Eileen P G Vining; Gretchen K Von Allmen; Judith L Weisenberg; Peter Widdess-Walsh; Melodie R Winawer Journal: Nature Date: 2013-08-11 Impact factor: 49.962
Authors: Heather E Olson; Nolwenn Jean-Marçais; Edward Yang; Delphine Heron; Katrina Tatton-Brown; Paul A van der Zwaag; Emilia K Bijlsma; Bryan L Krock; E Backer; Erik-Jan Kamsteeg; Margje Sinnema; Margot R F Reijnders; David Bearden; Amber Begtrup; Aida Telegrafi; Roelineke J Lunsing; Lydie Burglen; Gaetan Lesca; Megan T Cho; Lacey A Smith; Beth R Sheidley; Christelle Moufawad El Achkar; Phillip L Pearl; Annapurna Poduri; Cara M Skraban; Jennifer Tarpinian; Addie I Nesbitt; Dietje E Fransen van de Putte; Claudia A L Ruivenkamp; Patrick Rump; Nicolas Chatron; Isabelle Sabatier; Julitta De Bellescize; Laurent Guibaud; David A Sweetser; Jessica L Waxler; Klaas J Wierenga; Jean Donadieu; Vinodh Narayanan; Keri M Ramsey; Caroline Nava; Jean-Baptiste Rivière; Antonio Vitobello; Frédéric Tran Mau-Them; Christophe Philippe; Ange-Line Bruel; Yannis Duffourd; Laurel Thomas; Stefan H Lelieveld; Janneke Schuurs-Hoeijmakers; Han G Brunner; Boris Keren; Julien Thevenon; Laurence Faivre; Gary Thomas; Christel Thauvin-Robinet Journal: Am J Hum Genet Date: 2018-04-12 Impact factor: 11.025
Authors: Anne T Berg; Courtney Wusthoff; Renée A Shellhaas; Tobias Loddenkemper; Zachary M Grinspan; Russell P Saneto; Kelly G Knupp; Anup Patel; Joseph E Sullivan; Eric H Kossoff; Catherine J Chu; Shavonne Massey; Ignacio Valencia; Cynthia Keator; Elaine C Wirrell; Jason Coryell; John J Millichap; William D Gaillard Journal: Epilepsy Behav Date: 2019-06-07 Impact factor: 2.937