Rapid Targeted Genomics in Critically Ill Newborns
Rapid Targeted Genomics in Critically Ill Newborns
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DOI：
10.1542/peds.2016-2854
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发表时间：
2017-10-01
期刊：
影响因子：
8
通讯作者：
Wijmenga, Cisca
中科院分区：
文献类型：
--
作者：
van Diemen, Cleo C.;Kerstjens-Frederikse, Wilhelmina S.;Wijmenga, Cisca
背景技术背景：快速诊断性全基因组测序已在危重新生儿中进行了探索，希望能改善他们的临床护理，并取代耗时和/或侵入性的诊断检测。先前的一项回顾性研究显示，57%的患者诊断出了有希望的结果，但患者被高度选择为已知和可能的孟德尔疾病。我们的前瞻性研究的目的是评估的速度和产量的快速有针对性的基因组诊断的临床应用程序。方法：我们包括23名重症监护室在2年内小于12个月的儿童。常规临床评估和诊断后无法快速诊断。利用全基因组测序数据对3426个已知疾病基因进行了靶向分析。我们测量诊断率，周转时间，和临床consequence.RESULTS：基因诊断7例（30%），中位周转时间为12天（范围从5到23天）。我们鉴定了EPG 5基因（维西综合征）、RMND 1基因（氧化磷酸化缺陷-11）和EIF 2B 5基因（消失的白色物质）的复合杂合突变，以及KLHL 41基因（线状体肌病）、GFER基因（进行性线粒体肌病）和GLB 1基因（GM 1-神经节苷脂沉积症）的纯合突变。此外，一个1p36.33p36.32微缺失检测在儿童cardiomy.CONCLUSIONS：快速靶向基因组学结合拷贝数变异检测增加了重要的价值，在新生儿和儿科重症监护环境。它导致了30%的重症儿童的快速诊断，对他们来说，常规的临床检查是不成功的。
BACKGROUND: Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and/ or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of our prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application.METHODS: We included 23 critically ill children younger than 12 months in ICUs over a period of 2 years. A quick diagnosis could not be made after routine clinical evaluation and diagnostics. Targeted analysis of 3426 known disease genes was performed by using wholegenome sequencing data. We measured diagnostic yield, turnaround times, and clinical consequences.RESULTS: A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). We identified compound heterozygous mutations in the EPG5 gene (Vici syndrome), the RMND1 gene (combined oxidative phosphorylation deficiency-11), and the EIF2B5 gene (vanishing white matter), and homozygous mutations in the KLHL41 gene (nemaline myopathy), the GFER gene (progressive mitochondrial myopathy), and the GLB1 gene (GM1-gangliosidosis). In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy.CONCLUSIONS: Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.