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Original Investigation
July 31, 2017

Early-Life Epilepsies and the Emerging Role of Genetic Testing

Author Affiliations
  • 1Epilepsy Center, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
  • 2Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 3Department of Pediatrics, Oregon Health & Science University, Portland
  • 4Department of Neurology, Oregon Health & Science University, Portland
  • 5Division of Pediatric Neurology, Seattle Children’s Hospital, Seattle, Washington
  • 6Department of Neurology, University of Washington, Seattle
  • 7Department of Pediatrics, Weill Cornell Medicine, New York, New York
  • 8Department of Pediatrics, New York Presbyterian Hospital, New York, New York
  • 9Health Information Technology Evaluation Collaborative, New York, New York
  • 10Department of Human Genetics, Emory University, Atlanta, Georgia
  • 11Department of Neurology, University of California, San Francisco
  • 12Department of Neurology, Mayo Clinic, Rochester Minnesota
  • 13Department of Pediatrics, University of Michigan, Ann Arbor
  • 14Department of Pediatrics, The Ohio State University, Columbus
  • 15Department of Neurology, Nationwide Children’s Hospital, Columbus, Ohio
  • 16Department of Neurology, Children’s National Health System, George Washington University School of Medicine, Washington, DC
  • 17Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
  • 18Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland
  • 19Section of Neurology, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania
  • 20Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora
  • 21Department of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora
  • 22Division of Child Neurology, Stanford University, Palo Alto, California
  • 23Cook Children’s Health Care System, Jane and John Justin Neurosciences Center, Fort Worth, Texas
  • 24Division of Pediatric Neurology, Seattle Children’s Hospital, Seattle, Washington
  • 25Department of Pediatrics, University of Washington, Seattle
  • 26Department of Neurology, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 27Department of Pediatrics, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 28Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 29Department of Neurology, Massachusetts General Hospital, Boston
  • 30Center for Integrative Brain Research, University of Washington, Seattle
  • 31Seattle Children’s Research Institute, Seattle, Washington
  • 32Department of Pediatrics, University of Washington, Seattle
  • 33Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia
JAMA Pediatr. Published online July 31, 2017. doi:10.1001/jamapediatrics.2017.1743
Key Points

Question  What is the diagnostic yield of genetic testing when used for children with newly presenting early-life epilepsy?

Finding  In this cohort study of 775 children, diagnostic yields overall were 40%, with epilepsy gene-sequencing panels and whole-exome sequencing having substantially greater diagnostic yields than chromosomal microarray. In the absence of a clinically identified cause, testing yields were greater than 15% and as high as 47% depending on patient subgroups.

Meaning  Genetic testing, especially with sequencing-based methods, should be incorporated into the routine initial evaluation of early-life epilepsy.

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.

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