用于罕见孟德尔疾病基因鉴定的临床外显子组测序
Clinical exome sequencing for genetic identification of rare Mendelian disorders.
作者信息
Lee Hane, Deignan Joshua L, Dorrani Naghmeh, Strom Samuel P, Kantarci Sibel, Quintero-Rivera Fabiola, Das Kingshuk, Toy Traci, Harry Bret, Yourshaw Michael, Fox Michelle, Fogel Brent L, Martinez-Agosto Julian A, Wong Derek A, Chang Vivian Y, Shieh Perry B, Palmer Christina G S, Dipple Katrina M, Grody Wayne W, Vilain Eric, Nelson Stanley F
机构信息
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles2Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles.
Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles3Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles.
出版信息
JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.
IMPORTANCE
Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.
OBJECTIVE
To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.
DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.
MAIN OUTCOMES AND MEASURES
Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.
RESULTS
Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.
CONCLUSIONS AND RELEVANCE
In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
重要性
临床外显子组测序（CES）正迅速成为针对患有罕见遗传疾病个体的一种常见分子诊断测试。
目的
报告CES转诊的初始临床指征以及不同指征和不同测试类型的分子诊断率。
设计、设置和参与者：2012年1月至2014年8月期间，在加利福尼亚大学洛杉矶分校临床基因组中心，对814例连续的未确诊、疑似患有遗传疾病的患者进行了临床外显子组测序。临床外显子组测序采用三联体CES（同时对父母及其患病子女进行测序）以有效检测新生和复合杂合变异，或在无法获取父母样本时采用先证者CES（仅对患病个体进行测序）。
主要结局和指标
CES申请的临床指征、CES总体及表型亚组的分子诊断率，以及三联体CES和先证者CES之间分子诊断率的差异。
结果
在814例病例中，总体分子诊断率为26%（814例中的213例；95%置信区间，23% - 29%）。三联体CES的分子诊断率为31%（410例中的127例；95%置信区间，27% - 36%），先证者CES的分子诊断率为22%（338例中的74例；95%置信区间，18% - 27%）。在儿童发育迟缓病例（<5岁，n = 138）中，三联体CES病例的分子诊断率为41%（109例中的45例；95%置信区间，32% - 51%），先证者CES病例的分子诊断率为9%（23例中的2例，9%置信区间，1% - 28%）。三联体CES显著更高的诊断率（P值 = 0.002；优势比，7.4 [95%置信区间，1.6 - 33.1]）归因于新生和复合杂合变异的识别。
结论和意义
在这个未确诊、疑似患有遗传疾病的患者样本中，三联体CES与比先证者CES或传统分子诊断方法更高的分子诊断率相关。有必要开展更多旨在验证这些发现并探索这种方法对临床和经济结局影响的研究。
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