Ostrander Betsy E P, Butterfield Russell J, Pedersen Brent S, Farrell Andrew J, Layer Ryan M, Ward Alistair, Miller Chase, DiSera Tonya, Filloux Francis M, Candee Meghan S, Newcomb Tara, Bonkowsky Joshua L, Marth Gabor T, Quinlan Aaron R
1Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT USA.
2Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT USA.
NPJ Genom Med. 2018 Aug 13;3:22. doi: 10.1038/s41525-018-0061-8. eCollection 2018.
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.
早期婴儿癫痫性脑病（EIEE）是一种严重的癫痫综合征，在生命的最初几个月发病。虽然已知50多种不同基因的突变会导致EIEE，但目前基因检测板测试或全外显子测序的诊断率低于60%。我们对14名EIEE受试者进行了全基因组分析（WGA），包括全基因组测序和全面的变异发现方法，这些受试者之前的基因检测未能得出诊断结果。我们在已知的EIEE基因中鉴定出新生点突变和插入缺失突变以及新生结构重排，以及之前与EIEE无关的基因中的突变。在所有14名受试者中检测到致病或可能致病的突变，证明了WGA在减少EIEE临床诊断时间和成本方面的效用。虽然外显子测序可能检测到了14个致病突变中的12个，但其中12名患者中有3名在进行基因组测序之前接受了非诊断性外显子检测板测试。因此，鉴于测序成本持续下降，我们的结果支持将WGA与全面的变异发现方法结合使用，作为EIEE和其他遗传疾病临床诊断的有效策略。
