全外显子组测序在危重症新生儿单基因遗传病中的临床应用

Clinical application of whole exome sequencing in monogenic hereditary disorders in critically ill newborns

摘要:

目的 探讨全外显子组测序（WES）检测技术在危重症新生儿单基因遗传病中的临床应用价值及意义。方法 选取2016年6月至2018年12月收治的怀疑有遗传性疾病或临床诊断不明确的危重症新生儿为研究对象，采集患儿及父母全血标本进行WES检测。对检测出的基因变异进行分类，寻找与临床表现相关的变异，并进行Sanger测序验证。结果 共纳入新生儿45例，男22例，女23例，中位发病日龄为2.0 d。经分子诊断确诊单基因遗传病患儿12例，诊断阳性率为27%，中位确诊日龄为31.5 d，其中与部分临床表型相关、但经对患儿临床表型再次进行补充与分析后诊断为单基因遗传病者占42%（5/12）。确诊单基因遗传病的患儿经临床治疗后好转率为67%（8/12）。结论 WES检测技术是寻找危重症新生儿单基因遗传病基因变异的有力工具，并可在临床决策中起到关键作用，但数据结果的解读还需要临床医生结合患儿的表型与WES检测结果综合分析。

Abstract:

Objective To explore the value and significance of the clinical application of whole exome sequencing (WES) in monogenic hereditary disorders in critically ill newborns. Methods The critically ill newborns in the neonatal intensive care unit with suspected hereditary diseases or unclear clinical diagnosis from June 2016 to December 2018 were enrolled. The whole blood samples from both newborns and parents were collected for WES. The detected genetic mutations were classified, the mutations associated with clinical phenotypes were searched for, and Sanger sequencing was performed to verify the mutations. Results A total of 45 newborns were enrolled, including 22 males and 23 females, and the median age of onset was 2.0 days. Of the 45 newborns, 12 (27%) were confirmed with monogenic hereditary disorders by molecular diagnostics, and the median age at diagnosis was 31.5 days. Of the 12 newborns with monogenic hereditary disorders, 5 (42%) were partially associated with clinical phenotypes but confirmed with monogenic hereditary disorders by additional information supplement and analysis. The improvement rate of newborns with monogenic hereditary disorders was 67% (8/12) after treatment. Conclusions WES technology is a powerful tool for finding genetic mutations in monogenic hereditary disorders in critically ill newborns and can play a crucial role in clinical decision-making. However, a comprehensive interpretation of sequence data requires physicians to take the clinical phenotypes and the results of WES into consideration simultaneously.