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 Jr, Koh S. Early-Life Epilepsies and the Emerging Role of Genetic Testing. JAMA Pediatr. 2017 Sep 1;171(9):863-871.
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.
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.
Genetic diagnostic testing.
MAIN OUTCOMES AND MEASURES:
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%]).
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.
Based on tracking of outcomes for children with epilepsy, researchers concluded that genetic testing, particularly gene sequencing, should be incorporated into the initial evaluation of young children with epilepsy so that an optimal treatment plan can be devised.
Doctors often must tell parents of children with early-life epilepsy that they don't know why their child has seizures, but a new study suggests that they would have more answers if genetic testing was routinely done as part of the diagnostic workup…
In a July 31 online report in JAMA Pediatrics, the authors concluded that genetic testing, particularly gene sequencing, should be incorporated into the initial evaluation of young children with epilepsy so that an optimal treatment plan can be devised. Often genetic testing for epilepsy is not conducted until doctors exhaust traditional means of evaluation, such as neuroimaging and metabolic testing, the study authors said.
“Genetic testing can end the diagnostic odyssey and that is a huge thing,” said lead author Anne T. Berg, PhD, research professor of pediatrics at Ann & Robert H. Lurie Children's Hospital of Chicago and the Northwestern University Feinberg School of Medicine. She said the sooner a precise diagnosis can be made, the sooner a child can be started on the most appropriate therapy, which can help protect against seizures during a critical time of development and perhaps save on medical expenses…
Of the remaining 680 children, 327 (48 percent) underwent genetic testing, whether karyotyping, microarrays, epilepsy panels, whole exome sequencing, mitochondrial function gene panels and other targeted genetic investigations. Genetic testing identified pathogenic variants in 40 percent of the children who were tested.
“Aside from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9/11, 82 percent), metabolic diseases (11/14, 79 percent) and brain malformations (20/61, 33 percent),” the researchers reported. Genetic testing yielded a specific diagnosis in 25 percent of children for whom the cause of epilepsy would have been otherwise impossible to pinpoint.
The researchers found that in children with initially unexplained etiology, the diagnostic yield was substantially less for chromosome microarray, which is currently more commonly used, than it was for sequencing methods, including epilepsy panels and whole exome sequencing.
They noted that like magnetic resonance imaging, genetic tests “have substantial diagnostic yields regardless of clinical features, certainly higher than the many metabolic tests that are frequently ordered.”
They concluded that “genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluations of early-presenting ELE [early-life epilepsies] and not just reserved for those with severe presentations and poor outcomes.”
Fitzgerald, Susan. In the Clinic – Epilepsy: Why Researchers Say Genetic Testing Should Be Standard for Children with Early Life-Epilepsy. Neurology Today: October 5, 2017 - Volume 17 - Issue 19 - p 24–26