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, William D. Gaillard, Eric H. Kossoff, Ignacio Valencia, Kelly G. Knupp, Courtney Wusthoff, Cynthia Keator, William B. Dobyns, Nicole Ryan, Tobias Loddenkemper, Catherine J. ChuEdward J. Novotny, Sookyong Koh

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)863-871
Number of pages9
JournalJAMA Pediatrics
Volume171
Issue number9
DOIs
StatePublished - Sep 1 2017

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Genetic Testing
Epilepsy
Exome
Karyotyping
Pediatric Hospitals
Tuberous Sclerosis
Metabolic Diseases
Spasm
Age of Onset
Cytogenetics
Brain Injuries
Brain

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Berg, A. T., Coryell, J., Saneto, R. P., Grinspan, Z. M., Alexander, J. J., Kekis, M., ... Koh, S. (2017). Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatrics, 171(9), 863-871. https://doi.org/10.1001/jamapediatrics.2017.1743

Early-life epilepsies and the emerging role of genetic testing. / Berg, Anne T.; Coryell, Jason; Saneto, Russell P.; Grinspan, Zachary M.; Alexander, John J.; Kekis, Mariana; Sullivan, Joseph E.; Wirrell, Elaine C; Shellhaas, Renée A.; Mytinger, John R.; Gaillard, William D.; Kossoff, Eric H.; Valencia, Ignacio; Knupp, Kelly G.; Wusthoff, Courtney; Keator, Cynthia; Dobyns, William B.; Ryan, Nicole; Loddenkemper, Tobias; Chu, Catherine J.; Novotny, Edward J.; Koh, Sookyong.

In: JAMA Pediatrics, Vol. 171, No. 9, 01.09.2017, p. 863-871.

Research output: Contribution to journalArticle

Berg, AT, Coryell, J, Saneto, RP, Grinspan, ZM, Alexander, JJ, Kekis, M, Sullivan, JE, Wirrell, EC, Shellhaas, RA, Mytinger, JR, Gaillard, WD, Kossoff, EH, Valencia, I, Knupp, KG, Wusthoff, C, Keator, C, Dobyns, WB, Ryan, N, Loddenkemper, T, Chu, CJ, Novotny, EJ & Koh, S 2017, 'Early-life epilepsies and the emerging role of genetic testing', JAMA Pediatrics, vol. 171, no. 9, pp. 863-871. https://doi.org/10.1001/jamapediatrics.2017.1743
Berg AT, Coryell J, Saneto RP, Grinspan ZM, Alexander JJ, Kekis M et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatrics. 2017 Sep 1;171(9):863-871. https://doi.org/10.1001/jamapediatrics.2017.1743
Berg, Anne T. ; Coryell, Jason ; Saneto, Russell P. ; Grinspan, Zachary M. ; Alexander, John J. ; Kekis, Mariana ; Sullivan, Joseph E. ; Wirrell, Elaine C ; Shellhaas, Renée A. ; Mytinger, John R. ; Gaillard, William D. ; Kossoff, Eric H. ; Valencia, Ignacio ; Knupp, Kelly G. ; Wusthoff, Courtney ; Keator, Cynthia ; Dobyns, William B. ; Ryan, Nicole ; Loddenkemper, Tobias ; Chu, Catherine J. ; Novotny, Edward J. ; Koh, Sookyong. / Early-life epilepsies and the emerging role of genetic testing. In: JAMA Pediatrics. 2017 ; Vol. 171, No. 9. pp. 863-871.
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author = "Berg, {Anne T.} and Jason Coryell and Saneto, {Russell P.} and Grinspan, {Zachary M.} and Alexander, {John J.} and Mariana Kekis and Sullivan, {Joseph E.} and Wirrell, {Elaine C} and Shellhaas, {Ren{\'e}e A.} and Mytinger, {John R.} and Gaillard, {William D.} and Kossoff, {Eric H.} and Ignacio Valencia and Knupp, {Kelly G.} and Courtney Wusthoff and Cynthia Keator and Dobyns, {William B.} and Nicole Ryan and Tobias Loddenkemper and Chu, {Catherine J.} and Novotny, {Edward J.} and Sookyong Koh",
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TY - JOUR

T1 - Early-life epilepsies and the emerging role of genetic testing

AU - Berg, Anne T.

AU - Coryell, Jason

AU - Saneto, Russell P.

AU - Grinspan, Zachary M.

AU - Alexander, John J.

AU - Kekis, Mariana

AU - Sullivan, Joseph E.

AU - Wirrell, Elaine C

AU - Shellhaas, Renée A.

AU - Mytinger, John R.

AU - Gaillard, William D.

AU - Kossoff, Eric H.

AU - Valencia, Ignacio

AU - Knupp, Kelly G.

AU - Wusthoff, Courtney

AU - Keator, Cynthia

AU - Dobyns, William B.

AU - Ryan, Nicole

AU - Loddenkemper, Tobias

AU - Chu, Catherine J.

AU - Novotny, Edward J.

AU - Koh, Sookyong

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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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