Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases
Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases
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DOI：
10.1038/s41525-018-0053-8
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发表时间：
2018-07-09
影响因子：
5.3
通讯作者：
Kingsmore, Stephen F.
中科院分区：
文献类型：
--
作者：
Clark, Michelle M.;Starke, Zornitza;Kingsmore, Stephen F.
遗传病是导致儿童死亡的主要原因。全基因组测序(WGS)和全外显子组测序(WES)是诊断遗传病的较新方法，而染色体微阵列(CMA)已经成熟。在这里，我们通过系统回顾文献(2011年1月至2017年8月)和荟萃分析，遵循MOOSE/PRISMA指南，比较了WGS、WES和CMA在疑似遗传性疾病儿童中的诊断效用(已知疾病基因中致病、致病或可能致病基因的比率)和临床效用(因诊断而改变内科或外科治疗的比例)。在涉及20068名儿童的37项研究中，WGS(0.41，95%CI 0.34-0.48，I-2=44%)和WES(0.36，95%CI 0.33-0.40，I-2=83%)的诊断效用定性高于CMA(0.10，95%CI 0.08-0.12，I-2=81%)。在2017年发表的研究中，WGS的诊断效用显著高于CMA(P<；0.0001，I-2=13%和I-2=40%)。在以队列内比较为特征的研究中，WES的诊断效用显著高于CMA(P<；0.001，I-2=36%)。WGS和WES的诊断价值无显著差异。在对WGS/WES进行队列内比较的研究中，三胞胎的诊断可能性显著高于单胞胎(优势比2.04，95%0.1.62-2.56，I-212%；P<；0.0001)。WGS/WES的医院解释诊断效用(0.42，95%CI 0.38~0.45，I-2=48%)定性高于参考实验室(0.29，95%CI 0.27~0.31，I-2=49%)；这一差异在2017年发表的研究中显著(P<；0.0001，I-2=22%和I-2=26%)。WGS(0.27，95%CI 0.17~0.40，P=54%)和WES(0.17，95%CI 0.12~0.24，P=76%)均高于CMA(0.06，95%CI 0.05~0.07，I-2=42%)，差异有统计学意义(P<；0.0001)。综上所述，在疑似遗传病的儿童中，WGS/WES的诊断和临床实用价值大于CMA。WGS/WES诊断实用价值较高的亚组是TRIO和接受医院解释的亚组。WGS/WES应被认为是疑似遗传病儿童的一线基因组测试。
Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/ PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34-0.48, I-2 = 44%) and WES (0.36, 95% CI 0.33-0.40, I-2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08-0.12, I-2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I-2 = 13% and I-2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I-2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95%0 1.62-2.56, I-2 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38-0.45, I-2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27-0.31, I-2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I-2 = 22% and I-2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17-0.40, P = 54%) and WES (0.17, 95% CI 0.12-0.24, P = 76%) were higher than CMA (0.06, 95% CI 0.05-0.07, I-2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.