Clinical interpretation and implications of whole-genome sequencing.
Clinical interpretation and implications of whole-genome sequencing.
复制标题
DOI：
10.1001/jama.2014.1717
复制
发表时间：
2014-03-12
影响因子：
120.7
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
--
作者：
Dewey, Frederick E.;Grove, Megan E.;Pan, Cuiping;Goldstein, Benjamin A.;Bernstein, Jonathan A.;Chaib, Hassan;Merker, Jason D.;Goldfeder, Rachel L.;Enns, Gregory M.;David, Sean P.;Pakdaman, Neda;Ormond, Kelly E.;Caleshu, Colleen;Kingham, Kerry;Klein, Teri E.;Whirl-Carrillo, Michelle;Sakamoto, Kenneth;Wheeler, Matthew T.;Butte, Atul J.;Ford, James M.;Boxer, Linda;Ioannidis, John P. A.;Yeung, Alan C.;Altman, Russ B.;Assimes, Themistocles L.;Snyder, Michael;Ashley, Euan A.;Quertermous, Thomas
全基因组测序（WGS）越来越多地应用于临床医学，无论测序适应症如何，都有望发现具有临床意义的发现。检查WGS技术提供的临床相关遗传变异的覆盖率和一致性;量化WGS数据中的遗传性疾病风险和药物基因组学结果以及发现和解释所需的资源;并评估WGS结果提示的临床行动。一项对斯坦福大学医学中心招募的12名成年参与者的探索性研究，他们在2011年11月至2012年3月期间接受了WGS。一个多学科小组审查了所有可能报告的遗传学发现。五位医生建议根据遗传学发现进行初步临床随访。不同遗传疾病风险类别的基因组覆盖率和测序平台一致性，用于策划候选疾病风险变体的人-小时，训练有素的策展人和疾病遗传学数据库之间的解释一致性，遗传疾病风险和药物基因组学结果的负担，以及拟议临床随访的负担和评价者之间的一致性。根据测序平台的不同，10%至19%的遗传性疾病基因没有被单核苷酸变异发现的公认标准所覆盖。先前描述的单核苷酸遗传变异的基因型一致性较高（99%-100%），但小插入/缺失变异的基因型一致性较低（53%-59%）。每个参与者治疗90 - 127个遗传变异需要每个遗传变异54分钟的中位数（范围5-223分钟），导致专业人员之间的中等分类一致性（Gross κ，0.52; 95%CI，0.40-0.64），并将突变数据库中归类为致病的69%的遗传变异重新分类为不确定或不太重要的变异。在每个参与者中发现了2到6个个人疾病风险结果，包括与遗传性乳腺癌和卵巢癌有关的BRCA 1基因中的1个移码缺失。医生对测序结果的审查促使每位参与者考虑1至3次初始诊断测试和转诊的中位数，评估者对WGS结果用于临床随访的适用性达成了公平的一致意见（Fleiss κ，0.24; P <0.01）。在这项对12名志愿成人进行的探索性研究中，使用WGS与遗传性疾病基因的不完全覆盖、具有最高潜在临床效应的遗传变异检测的重现性低以及临床可报告结果的不确定性相关。在某些情况下，WGS将识别临床上可操作的遗传变异，从而避免早期医疗干预。在确定WGS在临床医学中的作用时，应考虑这些问题。
Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95%CI, 0.40-0.64), and reclassified 69%of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
全基因组关联研究的荟萃分析确定了东亚人 2 型糖尿病的 8 个新位点
影响因子：
30.8
作者：
Cho, Yoon Shin;Chen, Chien-Hsiun;Hu, Cheng;Long, Jirong;Ong, Rick Twee Hee;Sim, Xueling;Takeuchi, Fumihiko;Wu, Ying;Go, Min Jin;Yamauchi, Toshimasa;Chang, Yi-Cheng;Kwak, Soo Heon;Ma, Ronald C. W.;Yamamoto, Ken;Adair, Linda S.;Aung, Tin;Cai, Qiuyin;Chang, Li-Ching;Chen, Yuan-Tsong;Gao, Yutang;Hu, Frank B.;Kim, Hyung-Lae;Kim, Sangsoo;Kim, Young Jin;Lee, Jeannette Jen-Mai;Lee, Nanette R.;Li, Yun;Liu, Jian Jun;Lu, Wei;Nakamura, Jiro;Nakashima, Eitaro;Ng, Daniel Peng-Keat;Tay, Wan Ting;Tsai, Fuu-Jen;Wong, Tien Yin;Yokota, Mitsuhiro;Zheng, Wei;Zhang, Rong;Wang, Congrong;So, Wing Yee;Ohnaka, Keizo;Ikegami, Hiroshi;Hara, Kazuo;Cho, Young Min;Cho, Nam H.;Chang, Tien-Jyun;Bao, Yuqian;Hedman, Asa K.;Morris, Andrew P.;McCarthy, Mark I.;Takayanagi, Ryoichi;Park, Kyong Soo;Jia, Weiping;Chuang, Lee-Ming;Chan, Juliana C. N.;Maeda, Shiro;Kadowaki, Takashi;Lee, Jong-Young;Wu, Jer-Yuarn;Teo, Yik Ying;Tai, E. Shyong;Shu, Xiao Ou;Mohlke, Karen L.;Kato, Norihiro;Han, Bok-Ghee;Seielstad, Mark
通讯作者：
Seielstad, Mark
影响因子：
6.7
作者：
Crews, K. R.;Gaedigk, A.;Skaar, T. C.
通讯作者：
Skaar, T. C.
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：
168.9
作者：
Ashley, Euan A.;Butte, Atul J.;Wheeler, Matthew T.;Chen, Rong;Klein, Teri E.;Dewey, Frederick E.;Dudley, Joel T.;Ormond, Kelly E.;Pavlovic, Aleksandra;Morgan, Alexander A.;Pushkarev, Dmitry;Neff, Norma F.;Hudgins, Louanne;Gong, Li;Hodges, Laura M.;Berlin, Dorit S.;Thorn, Caroline F.;Sangkuhl, Katrin;Hebert, Joan M.;Woon, Mark;Sagreiya, Hersh;Whaley, Ryan;Knowles, Joshua W.;Chou, Michael F.;Thakuria, Joseph V.;Rosenbaum, Abraham M.;Zaranek, Alexander Wait;Church, George M.;Greely, Henry T.;Quake, Stephen R.;Altman, Russ B.
通讯作者：
Altman, Russ B.