Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort
Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort
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DOI：
10.1111/epi.16427
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发表时间：
2020-01-19
期刊：
影响因子：
5.6
通讯作者：
Poduri, Annapurna
中科院分区：
文献类型：
--
作者：
Rochtus, Anne;Olson, Heather E.;Poduri, Annapurna
我们评估了一组表型良好的癫痫患儿的全外显子组测序（WES）数据的系统分析和/或再分析的结果，这些患儿的遗传病因被怀疑是未知的。方法对125例小儿癫痫患者进行鉴定和分型。尽管临床测试包括染色体微阵列（57例患者），癫痫基因面板（n = 48），两者（n = 28）或WES (n = 8)，但在入组时病因不明。临床癫痫诊断包括发育性和癫痫性脑病（DEE）、发热性感染相关癫痫综合征、拉斯穆森脑炎和其他局灶性和全身性癫痫。我们分析了WES数据，并比较了有和没有事先进行临床基因检测的参与者的产率。总体而言，我们在40%（50/125）的研究参与者中发现了致病性或可能致病性变异。9例DEE患者在最近发表的临床试验中未被确认为癫痫相关的基因（FGF12、GABBR1、GABBR2、ITPA、KAT6A、PTPN23、RHOBTB2、SATB2）中存在遗传变异，8例患者在候选癫痫基因（CAMTA1、FAT3、GABRA6、HUWE1、PTCHD1）中存在遗传变异。90名参与者同时或随后进行了临床基因检测，这最终解释了26%（23/90）。在67名通过临床基因检测分子诊断“未解决”的参与者中，我们在17名（25%）中确定了致病或可能致病的变异。我们的数据表明，对于癫痫患者，特别是DEE或癫痫伴智力残疾的患者，应尽早考虑采用WES进行反复再分析。对表型良好的癫痫患者的WES数据进行严格分析，可以更广泛地了解基因特异性表型谱以及候选疾病基因鉴定。我们通过分析外显子组数据，并在某些情况下对外显子组数据进行再分析，阐明了遗传诊断随时间的动态性质，从而在具有先前各种临床测试策略的非诊断结果的参与者中识别出疾病相关变异。
Objective We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. Methods We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Results Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Significance Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.