Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Recommendations for clinical interpretation of variants found in non-coding regions of the genome
复制标题
对基因组非编码区域中发现的变异进行临床解释的建议
DOI：
10.1101/2021.12.28.21267792
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ellingford J
中科院分区：
文献类型：
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作者：
Ellingford J
背景大多数临床基因检测几乎完全集中在直接编码蛋白质的基因组区域。然而，非编码区变异在渗透性疾病中的重要作用越来越多地被证明，并且全基因组测序在临床诊断环境中的使用在大范围的遗传性疾病中正在增加。尽管如此，有没有现有的指导方针，主要是为蛋白质编码区的变异设计的当前指南应适应其他genomiccontext.MethodsWe的变异，召集了一个小组的9个临床和研究科学家广泛的专业知识，在临床变异的解释，在非编码区的变异的具体经验。该小组讨论和完善的初步草案的指导方针，然后进行了广泛的测试和审查外部groups.ResultsWe讨论的考虑因素，特别是在非编码区的基因组的变异。我们概述了如何定义候选调节元件，重点介绍了非编码区变异导致渗透性单基因疾病的机制示例，并概述了如何调整现有指南来解释这些变异。结论这些建议旨在增加可以临床解释的非编码区变异的数量和范围，这些变异与兼容的表型一起，可以导致新的诊断，并催化发现新的疾病机制。
BackgroundThe majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.MethodsWe convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.ResultsWe discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants.ConclusionsThese recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
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影响因子：
17.1
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
通讯作者：
MacArthur DG
由 NIPBL 基因 5-2 非翻译区突变引起的 Cornelia de Lange 综合征的父女传播
影响因子：
3.9
作者：
G. Borck;Mohamed Zarhrate;C. Cluzeau;E. Bal;J. Bonnefont;A. Munnich;V. Cormier;L. Colleaux
通讯作者：
L. Colleaux
影响因子：
9.8
作者：
Gasperini, Molly;Findlay, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
MRSD：一种新的定量方法，用于评估 RNA-seq 在孟德尔病错误剪接临床研究中的适用性
影响因子：
0.7
作者：
Charlie F. Rowlands;Algy Taylor;G. Rice;N. Whiffin;H. N. Hall;W. Newman;G. Black;R. O’Keefe;S. Hubbard;A. Douglas;D. Baralle;T. Briggs;J. Ellingford
通讯作者：
J. Ellingford
教员意见推荐 MEF2C 上游非编码区变异通过三种不同的功能丧失机制导致严重的发育障碍。
DOI：
--
发表时间：
2021
期刊：
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
影响因子：
--
作者：
H. Mefford
通讯作者：
H. Mefford