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Early-Life Epilepsies and the Emerging Role of Genetic Testing
Journal article   Open access   Peer reviewed

Early-Life Epilepsies and the Emerging Role of Genetic Testing

Anne T Berg, Jason Coryell, Russell P Saneto, Zachary M Grinspan, John J Alexander, Mariana Kekis, Joseph E Sullivan, Elaine C Wirrell, Renée A Shellhaas, John R Mytinger, …
JAMA pediatrics, v 171(9), pp 863-871
01 Sep 2017
DOI: https://doi.org/10.1001/jamapediatrics.2017.1743
PMID: 28759667
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1001/jamapediatrics.2017.1743View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Adolescent Child Child, Preschool Cohort Studies Epilepsy - genetics Female Follow-Up Studies Genetic Predisposition to Disease Genetic Testing - methods Humans Infant Male Prospective Studies United States
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. To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies. 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. Genetic diagnostic testing. Laboratory-confirmed pathogenic variant. 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%]). 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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Collaboration types
Domestic collaboration
Web of Science research areas
Pediatrics
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