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
Epilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
JAMA Pediatr. 2017 Sep 1;171(9):863-871. doi: 10.1001/jamapediatrics.2017.1743.
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.
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.
儿童早期癫痫往往是多种神经发育障碍的结果，其中大多数已被证明具有遗传起源。基因检测在这些癫痫初始评估中的作用尚未明确。
提供关于儿童早期癫痫基因检测的使用模式和诊断率的当代描述。
设计、设置和参与者：在这项前瞻性队列研究中，2012年3月1日至2015年4月30日期间，从美国17家儿科医院招募了新诊断为癫痫且发病年龄小于3岁的儿童，并对其进行了1年的随访。在795个被邀请的家庭中，775个同意参与。根据基因检测前获得的信息对癫痫病因进行临床诊断。确定细胞遗传学和基因测序研究的额外贡献。
基因诊断检测。
实验室确认的致病变异。
在该研究的775例患者中（367例女孩和408例男孩；发病年龄中位数为7.5个月[四分位间距，4.2 - 16.5个月]），95例（12.3%）有获得性脑损伤。在其余680例患者中，327例（48.1%）接受了各种形式的基因检测，其中327例儿童中有132例（40.4%；95%置信区间，37% - 44%）检测到致病变异：59例中的26例（44.1%）进行了核型分析，188例中的32例（17.0%）进行了微阵列分析，114例中的31例（27.2%）进行了癫痫相关基因检测板分析，33例中的11例（33.3%）进行了全外显子组测序，20例中的4例（20.0%）进行了线粒体基因检测板分析，94例中的28例（29.8%）进行了其他检测。44个变异在首次癫痫发作前被识别。除畸形综合征外，结节性硬化症患儿（11例中的9例[81.8%]）、代谢性疾病患儿（14例中的11例[78.6%]）和脑畸形患儿（61例中的20例[32.8%]）的致病率最高。在446例病因在未进行基因检测时仍不明的儿童中，共有180例（40.4%）接受了某种检测。180例儿童中有48例（26.7%；95%置信区间，18% - 34%）检测到致病变异。无论是否存在延迟、痉挛和年幼情况，诊断率均大于15%。癫痫相关基因检测板分析（96例中的28例[29.2%]；P <.001）和全外显子组测序（18例中的5例[27.8%]；P = 0.02）的诊断率高于染色体微阵列分析（101例中的8例[7.9%]）。
基因检测，尤其是广泛的测序方法，在新诊断的儿童早期癫痫中具有较高的诊断率，无论关键临床特征如何。强调测序检测的全面基因检测应纳入新出现的儿童早期癫痫的初始评估中，而不仅仅局限于那些表现严重和预后不良的患儿。
