Clinical Diagnostic Sequencing of Structural Variation

结构变异的临床诊断测序

• 批准号: 10683301
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 71.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683301
• 关键词: Address; Adoption; Algorithms; Amniocentesis; Area; Artificial Intelligence; Base Sequence; Bayesian Modeling; Benchmarking; Childhood; Clinical; Code; Computing Methodologies; DNA analysis; DNA sequencing; Data; Data Aggregation; Data Set; Development; Diagnosis; Diagnostic; Diagnostic tests; Early Diagnosis; Face; Fetus; First Pregnancy Trimester; Funding; Genes; Genetic; Genome; Genomic medicine; Genomics; Gestational Age; Goals; Healthcare; Human; Joints; Karyotype; Maternal-fetal medicine; Methods; Modeling; Molecular Abnormality; Mutation; Natural Selections; Non-Invasive Detection; Normal Cell; Pathogenicity; Patients; Pattern; Phenotype; Point Mutation; Population; Prenatal Diagnosis; Procedures; Process; Resolution; Resources; Sampling; Standardization; Structural defect; Technology; Testing; Tissues; Update; Validation; Variant; Visualization; aggregation database; algorithm development; analytical method; autism spectrum disorder; case control; causal variant; cell free fetal DNA; clinical diagnostics; cohort; congenital anomaly; cost; de novo mutation; dosage; early screening; exome sequencing; fetal; gene discovery; genetic testing; genome sequencing; high risk; improved; in silico; innovation; insertion/deletion mutation; machine learning method; neonatal death; next generation; novel; open source; prenatal; prenatal testing; programs; screening; standard of care; technology development; tool; transmission process; ultrasound; uptake; variant detection; whole genome

ABSTRACT Emerging genomic medicine initiatives are poised to impact prenatal and pediatric diagnostics, including assessment of fetal structural anomalies (FSAs) from amniocentesis and the rapid adoption of non-invasive prenatal screening (NIPS). Indeed, the rapid decrease in whole-genome sequencing (WGS) costs and the improved sophistication of analytic genomics methods has brought prenatal screening to a critical inflection point. Ongoing studies find improved diagnostic yields from WGS and whole exome sequencing (WES) over conventional karyotype and microarray (CMA); however, the technical, analytical, and interpretative challenges presented by structural variants (SVs) continue to confound sequence-based diagnostics. The field lacks standardized methods to interpret SVs from WGS and WES, yet these variants underlie a significant fraction of prenatal diagnoses, particularly for high risk fetuses with multiple congenital anomalies (MCAs). Our clinical SV program was initially formed to nucleate expertise in technology and algorithm development, variant interpretation, maternal-fetal medicine, and large-scale references to explore the impact of high-resolution SV detection in prenatal diagnostics. This resubmission builds upon the methods, resources, and discoveries from those studies to establish uniform approaches to jointly discover and interpret SVs, initially from amniocentesis and ultimately using non-invasive methods. We will focus on MCAs as exemplars of genomic diagnostics in severe clinical referrals. The discoveries from our initial funding period collectively suggest several critical advances could transform prenatal screening and genetic diagnostics, and we directly address three major barriers to these advances in this renewal: (1) Diagnostic yields from WES in FSAs are highly variable due to inconsistent methods and limited sensitivity to capture SVs. Aim 1 will benchmark diagnostic yields from WGS in MCA cases using our standardized open-source pipelines. (2) The genes contributing to the most severe fetal anomalies in humans remain largely unknown, as studies of MCAs have mostly been restricted to small cohorts and low-resolution CMA methods. Aim 2 will aggregate these severe fetal anomalies and perform uniform variant detection and joint association analyses of short variants and SVs from WES and WGS in FSA trios across multiple consortia, which we will compare to population-scale aggregated controls. (3) NIPS is ultra-low resolution and fails to capture most causal variant classes underlying MCAs. Aim 3 will benchmark an innovative approach to detect coding mutations and SVs from cffDNA, comparing yields to current NIPS and amniocentesis as the standard-of-care. Our team will thus leverage complementary expertise, novel methods, and unique patient resources to advance routine genomic screening in prenatal diagnostics.

抽象的 新兴的基因组医学举措有望影响产前和儿科诊断，包括 通过羊膜穿刺术评估胎儿结构异常（FSA）并快速采用非侵入性技术 产前筛查（NIPS）。事实上，全基因组测序（WGS）成本的迅速下降和 分析基因组学方法的复杂性的提高使产前筛查达到了一个关键的拐点。 正在进行的研究发现，WGS 和全外显子组测序 (WES) 的诊断率比 常规核型和微阵列（CMA）；然而，技术、分析和解释方面的挑战 结构变异（SV）所呈现的继续混淆基于序列的诊断。该领域缺乏 解释 WGS 和 WES 的 SV 的标准化方法，但这些变异是很大一部分的基础 产前诊断，尤其是患有多种先天性异常 (MCA) 的高危胎儿。我们的临床 SV 该计划最初的形成是为了集中技术和算法开发、变体方面的专业知识 解释、母胎医学和大规模参考资料来探索高分辨率 SV 的影响 产前诊断中的检测。这次重新提交建立在以下方法、资源和发现的基础上： 这些研究旨在建立统一的方法来共同发现和解释 SV，最初是通过羊膜穿刺术 最终使用非侵入性方法。我们将重点关注 MCA 作为基因组诊断的范例 严重的临床转诊。我们最初资助期间的发现共同提出了几个关键的问题 进步可以改变产前筛查和基因诊断，我们直接解决三个主要问题 此次更新中取得这些进展的障碍：(1) FSA 中 WES 的诊断结果变化很大，原因如下： 捕获 SV 的方法不一致且灵敏度有限。目标 1 将基准诊断率 使用我们的标准化开源管道在 MCA 案例中进行 WGS。 (2) 贡献最大的基因 人类严重的胎儿异常仍然很大程度上未知，因为对 MCA 的研究大多局限于 小队列和低分辨率 CMA 方法。目标 2 将汇总这些严重的胎儿异常情况并 对来自 WES 的短变异和 SV 进行统一变异检测和联合关联分析 跨多个联盟的 FSA 三人组中的 WGS，我们将其与群体规模的聚合对照进行比较。 (3) NIPS 的分辨率超低，无法捕获 MCA 底层的大多数因果变异类别。目标3将 对从 cffDNA 检测编码突变和 SV 的创新方法进行基准测试，将产量与 目前的护理标准是 NIPS 和羊膜穿刺术。因此，我们的团队将利用互补的专业知识， 新颖的方法和独特的患者资源可推进产前诊断中的常规基因组筛查。

项目成果

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

• DOI: 10.1038/ng.3720
• 发表时间: 2017-01
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Redin C;Brand H;Collins RL;Kammin T;Mitchell E;Hodge JC;Hanscom C;Pillalamarri V;Seabra CM;Abbott MA;Abdul-Rahman OA;Aberg E;Adley R;Alcaraz-Estrada SL;Alkuraya FS;An Y;Anderson MA;Antolik C;Anyane-Yeboa K;Atkin JF;Bartell T;Bernstein JA;Beyer E;Blumenthal I;Bongers EM;Brilstra EH;Brown CW;Brüggenwirth HT;Callewaert B;Chiang C;Corning K;Cox H;Cuppen E;Currall BB;Cushing T;David D;Deardorff MA;Dheedene A;D'Hooghe M;de Vries BB;Earl DL;Ferguson HL;Fisher H;FitzPatrick DR;Gerrol P;Giachino D;Glessner JT;Gliem T;Grady M;Graham BH;Griffis C;Gripp KW;Gropman AL;Hanson-Kahn A;Harris DJ;Hayden MA;Hill R;Hochstenbach R;Hoffman JD;Hopkin RJ;Hubshman MW;Innes AM;Irons M;Irving M;Jacobsen JC;Janssens S;Jewett T;Johnson JP;Jongmans MC;Kahler SG;Koolen DA;Korzelius J;Kroisel PM;Lacassie Y;Lawless W;Lemyre E;Leppig K;Levin AV;Li H;Li H;Liao EC;Lim C;Lose EJ;Lucente D;Macera MJ;Manavalan P;Mandrile G;Marcelis CL;Margolin L;Mason T;Masser-Frye D;McClellan MW;Mendoza CJ;Menten B;Middelkamp S;Mikami LR;Moe E;Mohammed S;Mononen T;Mortenson ME;Moya G;Nieuwint AW;Ordulu Z;Parkash S;Pauker SP;Pereira S;Perrin D;Phelan K;Aguilar RE;Poddighe PJ;Pregno G;Raskin S;Reis L;Rhead W;Rita D;Renkens I;Roelens F;Ruliera J;Rump P;Schilit SL;Shaheen R;Sparkes R;Spiegel E;Stevens B;Stone MR;Tagoe J;Thakuria JV;van Bon BW;van de Kamp J;van Der Burgt I;van Essen T;van Ravenswaaij-Arts CM;van Roosmalen MJ;Vergult S;Volker-Touw CM;Warburton DP;Waterman MJ;Wiley S;Wilson A;Yerena-de Vega MC;Zori RT;Levy B;Brunner HG;de Leeuw N;Kloosterman WP;Thorland EC;Morton CC;Gusella JF;Talkowski ME
• 通讯作者: Talkowski ME

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

• DOI: 10.1016/j.cell.2018.02.011
• 发表时间: 2018-02-22
• 期刊: Cell
• 影响因子: 64.5
• 作者: Aneichyk T;Hendriks WT;Yadav R;Shin D;Gao D;Vaine CA;Collins RL;Domingo A;Currall B;Stortchevoi A;Multhaupt-Buell T;Penney EB;Cruz L;Dhakal J;Brand H;Hanscom C;Antolik C;Dy M;Ragavendran A;Underwood J;Cantsilieris S;Munson KM;Eichler EE;Acuña P;Go C;Jamora RDG;Rosales RL;Church DM;Williams SR;Garcia S;Klein C;Müller U;Wilhelmsen KC;Timmers HTM;Sapir Y;Wainger BJ;Henderson D;Ito N;Weisenfeld N;Jaffe D;Sharma N;Breakefield XO;Ozelius LJ;Bragg DC;Talkowski ME
• 通讯作者: Talkowski ME

Mapping and phasing of structural variation in patient genomes using nanopore sequencing.

• DOI: 10.1038/s41467-017-01343-4
• 发表时间: 2017-11-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Cretu Stancu M;van Roosmalen MJ;Renkens I;Nieboer MM;Middelkamp S;de Ligt J;Pregno G;Giachino D;Mandrile G;Espejo Valle-Inclan J;Korzelius J;de Bruijn E;Cuppen E;Talkowski ME;Marschall T;de Ridder J;Kloosterman WP
• 通讯作者: Kloosterman WP

A novel microduplication of ARID1B: Clinical, genetic, and proteomic findings.

• DOI: 10.1002/ajmg.a.38327
• 发表时间: 2017-09
• 期刊: American journal of medical genetics. Part A
• 作者: Seabra CM;Szoko N;Erdin S;Ragavendran A;Stortchevoi A;Maciel P;Lundberg K;Schlatzer D;Smith J;Talkowski ME;Gusella JF;Natowicz MR
• 通讯作者: Natowicz MR