Genomic Ascertainment - Clinical and Behavioral Aspects

预测基因组医学或精确基因组医学具有最高的医学重要性，是一个活跃的研究领域。2006年，早在外显子组和基因组测序普及之前，我们就启动了ClinSeq项目，开始对全基因组罕见变异的回归进行试点（Biesecker等人，genome Res 2009）。我们通过在基因组中寻找可用于临床护理、生殖风险、药物遗传学和其他用途的高外显率变异，不断扩大我们在这一领域的工作。我的愿景是，基因组是一种医疗保健资源，而不是一项测试，而且这种医疗保健资源的成本可以在个人的一生中摊销，即使在它的主要用途完成很久之后。事实上，正是我们在ClinSeq上的工作，巩固了我们在2013年发布的关于次要发现（机会性筛查）的建议（Green等人，Genet Med 2013）。这些建议最初非常有争议，但经过一些修改，现在已经成为公认的临床实践，这是我们如何改变医学实践的一个例子。该论文被引用超过1200次，也成为多家临床检测实验室健康筛查基因集的依据。ClinSeq在向该领域证明，基因组和外显子组可以在健康人群中进行分析，并在最小的不良后果下返回结果，消除了对焦虑、抑郁、医疗保健过度使用和其他假设风险的普遍恐惧。ClinSeq也是CSER（临床测序探索性研究）联盟的创始成员，该联盟联合了六个研究中心，在医疗保健环境中试点基因组学。在参加了评估CSER申请的研究小组后，我加入了CSER，原因是这将有利于ClinSeq和其他中心的共同努力和经验。CSER已经停止了对校外网站的进一步资助，我们正在逐步减少与他们的合作。

Predictive genomic medicine or precision genomic medicine is of the highest medical importance and is an active area of research. We began piloting the return of genome-wide rare variants with the inception of the ClinSeq program in 2006, well before exome and genome sequencing became widespread (Biesecker et al., Genome Res 2009). We have continually expanded our work in this area by searching the genome for high penetrance variants that could be useful for clinical care, reproductive risks, pharmacogenetics, and other uses. My vision is that the genome is a health care resource, not a test, and that the cost of this health care resource can be amortized over the lifetime of an individual, long after its primary indicated usage is accomplished. Indeed, it was our work on ClinSeq that undergirded the recommendations we made for secondary findings (opportunistic screening) that were released in 2013 (Green et al., Genet Med 2013) These recommendations were initially highly controversial but with some amendments have now settled into accepted clinical practice an example of how we aim to change the practice of medicine. This paper has been cited more than 1,200 times and has also become the basis of a number of clinical testing laboratories health screening gene sets. ClinSeq has also been a leader in demonstrating to the field that genomes and exomes can be analyzed in healthy people and results returned, with minimal adverse consequences, dispelling the widespread fears about anxiety, depression, health care over-utilization, and other hypothetical risks. ClinSeq was also a charter member of the CSER (Clinical Sequencing Exploratory Research) consortium which allied six research centers to pilot genomics in health care settings. I joined CSER after participating in the study section that evaluated the CSER applications, reasoning that it would be beneficial for ClinSeq and for the other centers to pool efforts and experiences. CSER has ended further grants to extramural sites and we are winding down our collaboration with them. Genomic medicine has at its foundation prediction predicting phenotype based on genotype. To address this foundational challenge, we need to develop research modes that can model and test the predictive power of genomic variants. Resources such as gnomAD provide critical data on population prevalence but are seriously limited with respect to phenotype data. The UK BioBank is supporting genotype ascertainment, but its data are limited to pre-hoc phenotypes and blood samples and participants cannot be re-contacted. There is thus a compelling need for the capacity to perform bespoke phenotyping based on genotypes. Another major bottleneck in predictive genomic medicine is the return of results. The standard clinical model is for a physician or genetic counselor to meet with a patient for an individual session to describe the results, review the clinical implications, and provide genetic counseling and/or recurrence risks. This is obviously not scalable, and the field is in urgent need of alternative approaches to this challenge the variants from an exome (much less a genome) cannot be returned to a participant with this model. While most presume that this means that exomes and genomes need to be throttled or filtered down to just a single or few clinically relevant variants that can be returned using the standard model, the question should be asked as to whether alternative means to results return can be devised. Our efforts to increase the throughput of return of results lead us to set up a randomized controlled trial comparing standard genetic counselor-provided in person return of results to return of results with a web-based platform (Biesecker et al., JAMA Intern Med 2018). We have followed this work with additional analyses showing that there was no significant measurable added value of genetic counseling on top of information provision, either by web or counselor (Lewis et al., Am J Hum Genet 2018), we have also followed up with an analysis of perceptions of uncertainty amongst the recipients of these carrier results, (Umstead et al., Transl Behav Med In Press). In addition, we have undertaken a significant effort to better understand secondary variants in the research setting. We have now undertaken a major project to provide phenotyping for individuals suspected to have malignant hyperthermia susceptibility in collaboration with NIHCC neurosurgery and the USUHS ex vivo muscle testing laboratory.