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) 是一种毁灭性的癫痫综合征，在生命的最初几个月内发病。尽管已知超过 50 个不同基因的突变会导致 EIEE，但目前基因组测试或全外显子组测序的诊断率低于 60%。我们对 14 名 EIEE 受试者进行了全基因组分析 (WGA)，其中包括全基因组测序和综合变异发现方法，这些受试者之前的基因测试尚未得出诊断结果。我们鉴定了已知 EIEE 基因中的从头突变和 INDEL 突变以及从头结构重排，以及以前与 EIEE 不相关的基因突变。在所有 14 名受试者中检测到致病性或可能致病性突变，证明了 WGA 在减少 EIEE 临床诊断的时间和成本方面的效用。虽然外显子组测序可能已检测到 14 种因果突变中的 12 种，但 12 名患者中的 3 名在基因组测序之前接受了非诊断性外显子组检测。因此，鉴于测序成本持续下降，我们的结果支持使用 WGA 和全面的变异发现作为 EIEE 和其他遗传疾病临床诊断的有效策略。