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Evaluation of First-Degree Relatives after Sudden Unexplained Death

不明原因猝死后一级亲属的评估

基本信息

批准号：
10217228
负责人：
Robert Gregory Webster
金额：
$ 19万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217228
关键词：
Age Age-Years Arrhythmia Autopsy Bioinformatics Candidate Disease Gene Cardiac Cessation of life Clinical Clinical Research Communities Computerized Medical Record Counseling DNA Data Databases Diagnosis Diagnostic Disease Echocardiography Electrocardiogram Ensure Etiology Evaluation Event Exercise Family Family member First Degree Relative Frequencies Funding Future Genes Genetic Genetic Diseases Genetic Research Genetic Risk Genome Genotype Goals Grant Guidelines Heart Abnormalities Hypertrophic Cardiomyopathy Individual Investigation K-Series Research Career Programs Knowledge Lead Link Long QT Syndrome Medical Examiners Medical Genetics Mentors Mission Molecular Molecular Abnormality Morbidity - disease rate Multicenter Trials Outcome Parents Pathogenicity Pathway interactions Phenotype Physicians Population Predisposition Probability Public Health Research Research Personnel Resources Risk Risk Assessment Signal Transduction Source Standardization Sudden Death Syndrome Testing Training Treadmill Tests United States National Institutes of Health Universities Variant career development clinical phenotype clinical practice clinical risk cohort congenital heart disorder database of Genotypes and Phenotypes de novo mutation experience gene discovery genetic approach genetic profiling genetic testing genetic variant genome sequencing heart function heart rhythm high risk improved inherited cardiomyopathy innovation member mortality novel patient oriented phenome prevent prospective research clinical testing risk stratification skills translational genetics transmission process whole genome

项目摘要

PROJECT SUMMARY / ABSTRACT Sudden unexplained death (SUD) is a tragic event and genetic disorders of heart rhythm and function have been demonstrated in approximately 30% of SUD cases. Any SUD event is a dramatic signal that first-degree relatives require risk stratification. Evaluation of first-degree relatives of a SUD victim is limited by several important gaps in knowledge. First, studies have not prospectively evaluated the rate of transmitted versus de novo mutations in SUD cases when data from molecular autopsy are available. The implications of molecular autopsy for surviving family members depends on the probability of transmitted pathogenic variants. Second, when molecular autopsy is not performed, the value of genetic testing remains unknown for first-degree relatives. Better genetic risk stratification in this population will improve family diagnosis rates and improve counseling. Finally, genetic risk stratification of pathogenic and likely pathogenic variants in families with SUD depends on expanding the list of genes that may harbor pathogenic variants. The project has three specific aims: 1) Determine the frequency of transmitted versus de novo pathogenic and likely pathogenic variants in SUD; 2) Establish the yield of whole genome evaluation in phenotype-positive relatives of a SUD victim; and 3) Use whole genome sequencing (WGS) to identify novel candidate genes associated with SUD. The proposed research is innovative because it uses a close partnership between a multi-state consortium of medical examiner's offices and a nationally-recognized clinical and genetics center to produce a detailed genotype and phenotype evaluation of both SUD victims and their first-degree relatives using WGS. The proposed research is significant because the data generated from this project will improve the evaluation and management of first-degree relatives of SUD victims. Phenotype-genotype correlations will improve counseling. Finally, targeting treatment to those relatives at highest risk for events should decrease further sudden death in the population. This project will advance the candidate's overall training goal, which is to become an independent patient-oriented researcher, with expertise in the genetic diseases that impact SUD. This grant supplements the candidate's background in clinical research and public health by providing an opportunity for focused training in genetics and bioinformatics. Through coursework and practical training in WGS, the candidate will achieve relevant expertise and create a genotype-phenotype database that can be expanded to test additional hypotheses. The candidate's exceptionally strong mentoring team at Northwestern University and the robust resources for translational genetic research dedicated to Dr. Webster's training create a tremendous opportunity for career development and will contribute to the long-term goal of decreasing mortality in first-degree relatives after a sudden unexpected death event.

项目总结/摘要不明原因的猝死（SUD）是一个悲剧性事件，心脏节律和功能的遗传性疾病已经被发现。在大约30%的SUD病例中证实。任何SUD事件都是一个戏剧性的信号，需要进行风险分层。对SUD受害者一级亲属的评估受到以下几个重要差距的限制：知识首先，研究没有前瞻性地评估遗传性突变与新生突变的比率，当分子尸检数据可用时，SUD病例。分子解剖对幸存者的影响家庭成员的致病性取决于传播变异的概率。第二，当分子解剖如果没有进行基因检测，那么基因检测的价值对于一级亲属来说仍然是未知的。更好的遗传风险对这一人群进行分层将提高家庭诊断率并改善咨询。最后，遗传风险 SUD家族中致病性和可能致病性变异的分层取决于扩大可能携带致病变异的基因。该项目有三个具体目标：1）确定传播与新生致病的频率， SUD中可能的致病性变体; 2）在表型阳性亲属中建立全基因组评估的产量使用全基因组测序（WGS）来鉴定与SUD受害者相关的新候选基因。 SUD。拟议中的研究是创新的，因为它使用了一个多州财团之间的密切伙伴关系，法医办公室和国家认可的临床和遗传学中心，以产生详细的使用WGS对SUD受害者及其一级亲属进行基因型和表型评估。拟议研究意义重大，因为该项目产生的数据将改善评估和管理一级亲属的名单表型-基因型相关性将改善咨询。最后，瞄准对那些事件风险最高的亲属进行治疗应进一步减少人口中的猝死。这个项目将推进候选人的整体培训目标，这是成为一个独立的病人为导向研究人员，具有影响SUD的遗传疾病的专业知识。这项补助金补充了候选人的通过提供遗传学重点培训的机会，提供临床研究和公共卫生背景，生物信息学通过WGS的课程和实践培训，候选人将获得相关专业知识并创建一个基因型-表型数据库，可以扩展到测试其他假设。候选人的西北大学非常强大的指导团队和强大的转基因资源致力于韦伯斯特博士培训的研究为职业发展创造了巨大的机会，有助于降低一级亲属在意外猝死后的死亡率的长期目标活动

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-invasive Risk Stratification in Pediatric Ventricular Pre-excitation.

小儿心室预激的无创风险分层。

DOI：
10.1007/s00246-020-02285-3
发表时间：
2020
期刊：
Pediatric cardiology
影响因子：
1.6
作者：
Khaznadar,Rana;Chandler,StephanieF;Chaouki,ASami;Tsao,Sabrina;Webster,Gregory
通讯作者：
Webster,Gregory

Biventricular Assist Device Support for Intractable Arrhythmias From Histiocytoid Cardiomyopathy.

DOI：
10.1097/mat.0000000000001715
发表时间：
2022-11-01
期刊：
ASAIO JOURNAL
影响因子：
4.2
作者：
Magnetta, Defne A.;Reichhold, Allison;Thrush, Philip T.;Monge, Michael;Webster, Gregory;Joong, Anna
通讯作者：
Joong, Anna

Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology.

DOI：
10.1002/jgc4.1313
发表时间：
2021-03
期刊：
Journal of genetic counseling
影响因子：
1.9
作者：
Cherny S;Olson R;Chiodo K;Balmert LC;Webster G
通讯作者：
Webster G

Life-threatening arrhythmias with autosomal recessive TECRL variants.

DOI：
10.1093/europace/euaa376
发表时间：
2020-12
期刊：
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
影响因子：
0
作者：
G. Webster;E. Aburawi;M. Chaix;Stephanie F. Chandler;R. Foo;A. Islam;J. Kammeraad;J. Rioux;L. Al-Gazali;Md. Zahidus Sayeed;T. Xiao;Han Zhang;Lijian Xie;Cuilan Hou;Alexander Ing;K. Yap;A. Wilde;Z. Bhuiyan
通讯作者：
G. Webster;E. Aburawi;M. Chaix;Stephanie F. Chandler;R. Foo;A. Islam;J. Kammeraad;J. Rioux;L. Al-Gazali;Md. Zahidus Sayeed;T. Xiao;Han Zhang;Lijian Xie;Cuilan Hou;Alexander Ing;K. Yap;A. Wilde;Z. Bhuiyan

Right ventricular septal pacing via transmural approach for resynchronization in a child with postoperative heart block.