Diagnostic yield in epileptic encephalopathies is improved by genome sequencing and re-analysis

Objective: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).

Methods: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray (CMA), and either research ES (n=15) or diagnostic MGP (n=15).

Results: 8 diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants which now had additional evidence for pathogenicity. 11 diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n=10) involved genes not included in the panel, particularly in individuals with post-neonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features and/or multi-organ involvement.  42% of diagnoses were autosomal recessive or X-chromosome linked.

Conclusion: WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n=3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel non-coding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

研究目的：评估相较于外显子组测序（Exome Sequencing，ES）与多基因检测面板（Multigene Panel，MGP），全基因组测序（Whole Genome Sequencing，WGS）在发育性癫痫性脑病（Developmental and Epileptic Encephalopathies，DEE）的分子诊断中的优势与局限性。
研究方法：本研究对30例经过全面表型分型的发育性癫痫性脑病患者核心家系样本进行了全基因组测序。这些样本在接受一线检测（包括染色体微阵列分析（Chromosomal Microarray，CMA）、研究级外显子组测序（n=15）或诊断级多基因检测面板（n=15））后仍未获得明确诊断。
研究结果：在先前接受过外显子组测序的15例患者中，共检出8例明确诊断，检出率为53%：其中3例携带复杂结构变异；另外5例的变异虽可通过外显子组测序检出，但本研究补充了其致病性相关证据。在15例多基因检测面板结果阴性的患者中，共检出11例明确诊断，检出率为68%；其中多数（n=10）的致病基因未被该检测面板覆盖，此类情况尤其多见于癫痫起病于新生儿期后的患者，以及表现更为复杂的患者（包括伴运动障碍、畸形特征和/或多器官受累者）。本研究中42%的明确诊断为常染色体隐性遗传或X连锁遗传。
研究结论：相较于外显子组测序，全基因组测序的诊断检出率提升主要源于其对复杂结构变异的检出（共3例）。而更高的诊断检出率更多归因于二次分析的效能，而非全基因组测序平台本身的固有优势。未来仍需开展进一步研究，以辅助评估新型非编码区变异与复杂结构变异的致病性，并进一步提升发育性癫痫性脑病及其他神经遗传疾病患者的诊断检出率。