Molecular Diagnostic Outcomes from 700 Cases: What Can We Learn from a Retrospective Analysis of Clinical Exome Sequencing?
Molecular Diagnostic Outcomes from 700 Cases: What Can We Learn from a Retrospective Analysis of Clinical Exome Sequencing?
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DOI：
10.1016/j.jmoldx.2021.12.002
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发表时间：
2022-03
影响因子：
4.1
通讯作者：
Santani, Avni B.
中科院分区：
文献类型：
--
作者：
Murrell, Jill R.;Nesbitt, Addie May, I;Baker, Samuel W.;Pechter, Kieran B.;Balciuniene, Jorune;Zhao, Xiaonan;Denenberg, Elizabeth H.;DeChene, Elizabeth T.;Wu, Chao;Jayaraman, Pushkala;Cao, Kajia;Gonzalez, Michael;Devoto, Marcella;Testori, Alessandro;Monos, John D.;Dulik, Matthew C.;Conlin, Laura K.;Luo, Minjie;Gibson, Kristin McDonald;Guan, Qiaoning;Sarmady, Mahdi;Bhoj, Elizabeth;Helbig, Ingo;Zackai, Elaine H.;Bedoukian, Emma C.;Wilkens, Alisha;Tarpinian, Jennifer;Izumi, Kosuke;Skraban, Cara M.;Deardorff, Matthew A.;Medne, Livija;Krantz, Ian D.;Krock, Bryan L.;Santani, Avni B.
临床外显子组测序（CES）有助于罕见遗传疾病的诊断。在此，我们报告了在费城儿童医院分析的700例儿童病例中导致疾病的遗传改变的分子诊断率和谱。总诊断率为23%，其中3例有不止一种分子诊断，2.6%有继发/额外发现。在另外8.4%的病例中报告了候选基因发现。诊断率最高的临床适应症是神经发育障碍（包括癫痫发作），而免疫和肿瘤相关适应症与分子诊断呈负相关。关于基因组在人类疾病中的作用的知识的迅速扩展需要对CES样品进行重新分析。为了捕捉这些新发现，对一部分病例（n = 240）进行了重新分析，提高了诊断率。我们描述了我们在儿科环境中报告CES结果的经验，包括报告继发性发现，报告新发现的遗传条件，以及重新检查阴性检测结果。最后，我们强调了与实现CES工作流的关键更新相关的挑战。虽然这些更新是必要的，但它们需要实验室投入时间和资源。总之，这些数据证明了外显子组测序和再分析的临床实用性，同时强调了在临床实验室中持续改进CES测试的关键考虑因素。
Clinical exome sequencing (CES) aids in the diagnosis of rare genetic disorders. Herein, we report the molecular diagnostic yield and spectrum of genetic alterations contributing to disease in 700 pediatric cases analyzed at the Children's Hospital of Philadelphia. The overall diagnostic yield was 23%, with three cases having more than one molecular diagnosis and 2.6% having secondary/additional findings. A candidate gene finding was reported in another 8.4% of cases. The clinical indications with the highest diagnostic yield were neurodevelopmental disorders (including seizures), whereas immune- and oncology-related indications were negatively associated with molecular diagnosis. The rapid expansion of knowledge regarding the genome's role in human disease necessitates reanalysis of CES samples. To capture these new discoveries, a subset of cases (n = 240) underwent reanalysis, with an increase in diagnostic yield. We describe our experience reporting CES results in a pediatric setting, including reporting of secondary findings, reporting newly discovered genetic conditions, and revisiting negative test results. Finally, we highlight the challenges associated with implementing critical updates to the CES workflow. Although these updates are necessary, they demand an investment of time and resources from the laboratory. In summary, these data demonstrate the clinical utility of exome sequencing and reanalysis, while highlighting the critical considerations for continuous improvement of a CES test in a clinical laboratory.
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DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Baker, Samuel W.;Murrell, Jill R.;Santani, Avni B.
通讯作者：
Santani, Avni B.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
9.8
作者：
Dias C;Estruch SB;Graham SA;McRae J;Sawiak SJ;Hurst JA;Joss SK;Holder SE;Morton JE;Turner C;Thevenon J;Mellul K;Sánchez-Andrade G;Ibarra-Soria X;Deriziotis P;Santos RF;Lee SC;Faivre L;Kleefstra T;Liu P;Hurles ME;DDD Study;Fisher SE;Logan DW
通讯作者：
Logan DW
影响因子：
8.8
作者：
Powis, Zoe;Hagman, Kelly D. Farwell;Tang, Sha
通讯作者：
Tang, Sha