Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data.
Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data.
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DOI：
10.1371/journal.pgen.1005496
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Ashley EA
中科院分区：
文献类型：
--
作者：
Dewey FE;Grove ME;Priest JR;Waggott D;Batra P;Miller CL;Wheeler M;Zia A;Pan C;Karzcewski KJ;Miyake C;Whirl-Carrillo M;Klein TE;Datta S;Altman RB;Snyder M;Quertermous T;Ashley EA
高通量测序促进了基因组测序成本的急剧下降，促使人们预测通过诊断和治疗策略的基因个性化将引发医学革命。 There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed.在这里，我们提出了一系列方法来鉴定与临床关联的遗传变异和基因型，分阶段遗传数据并使用孟德尔遗传进行质量控制，并提供有关罕见病表型风险和单个个体和父母子三人对药物治疗反应的预测遗传信息。我们展示了这些方法在十二名无关成年人的全基因组序列数据中的疾病和药物反应预测的应用，以及在一名患有明显单纯性先天性室性心律失常的父母子三人组中发现疾病基因的应用。 In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals.我们还提名了先天性心律失常中的一个新候选基因 ATP2B4，并提供了使用该框架发现的变异体的调节作用的实验证据。 Technological advances have dramatically reduced the cost of sequencing the human genome.已经开发出了用于分析跨家庭此类数据的工具，包括临床重要变异的注释和用于个性化药物处方的变异聚合，但很少有公开可用的。 Here we describe such tools then demonstrate their application in several distinct data sets. In particular, we use the tools to define the genetic basis of a new congenital arrhythmia syndrome.
High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework. Technological advances have dramatically reduced the cost of sequencing the human genome. Tools for analyzing such data across families including annotation of clinically important variants and aggregation of variants for personalizing drug prescriptions have been developed but few are publically available. Here we describe such tools then demonstrate their application in several distinct data sets. In particular, we use the tools to define the genetic basis of a new congenital arrhythmia syndrome.