Return of Genomic Results and Estimating Penetrance in Population-Based Cohorts

项目总结/摘要 外显子组和基因组测序（GS）越来越多地在大规模人类研究中进行 研究，为研究人员创造了关于是否以及如何将遗传发现返回给参与者的问题。 然而，关于这种回报对研究参与者和调查者的影响，存在着严重的知识差距， 如何有效地识别和确认这些变体，以及如何提供关于其 特别是在基于人口的研究的参与者和代表性不足的人中 少数群体迫切需要关于这些问题的经验数据。最近，从7603名儿童身上收集的DNA FHS和杰克逊心脏研究（JHS，n = 3，406）中的个体 作为NHLBI精准医学跨组学（TOPMed）计划的一部分进行测序，其中2，885人在 FHS和JHS中的2，674人仍然活着。据估计，这些人中有1-2%携带有害变异 （定义为致病性或可能致病的变体，其对于显性病症是杂合的或双等位基因的） 对于隐性疾病）在59个基因之一的可操作的条件，美国医学院 遗传学和基因组学建议在临床测序中退回，无论适应症如何。 在本研究的目标1中，我们将开发并实施个人基因组结果返回流程 注意到在这59个基因中的一个中有有害的变异，并评估医疗，行为和经济 在社区研究人群中返回这些信息的相关结果。为 在Aim中，解释基因组结果以识别真正的致病性变异是一个高度劳动密集型的过程， 2我们将改进和应用FHS/JHS基因组的高通量筛选方法， 在另外4，572个疾病相关的突变中， 孟德尔疾病（不会被退回），同时降低了突变的错误发现率， 确定是良性的在目标3中，我们将回顾现有的表型数据，并比较文献记载的和自我研究的数据。 报告的表型变异分类的参与者谁做，不，携带有害的变异，在所有 4,631个孟德尔疾病相关基因通过比较基因型和表型数据，我们将完善一个新的 估计总反射率的粗略措施的方法，并为产生更多的 在更大的样本量中精确估计的最大值。

PROJECT SUMMARY/ABSTRACT Exome and genome sequencing (GS) are increasingly conducted within large-scale human research studies, creating questions for investigators about whether and how to return genetic findings to participants. Yet critical knowledge gaps exist about the impact of such return on research participants and investigators, how to efficiently identify and confirm such variants, and how to provide accurate estimates about their penetrance, particularly among participants in population-based studies and those who are underrepresented minorities. Empirical data on these questions are urgently needed. Recently, DNA collected from 7,603 individuals in the Framingham Heart Study (FHS, n=4,197) and the Jackson Heart Study (JHS, n=3,406) were sequenced as part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, of whom 2,885 in the FHS and 2,674 in the JHS, are living. An estimated 1-2% of these individuals carry a detrimental variant (defined as pathogenic or likely pathogenic variants that are heterozygous for dominant conditions or bi-allelic for recessive conditions) in one of 59 genes for actionable conditions that the American College of Medical Genetics and Genomics recommends be returned in clinical sequencing, regardless of indication. In Aim 1 of this study, we will develop and implement a genomic return of results process for individuals noted to have detrimental variants in one of these 59 genes, and evaluate medical, behavioral and economic outcomes associated with returning this information in community-based research populations. As the interpretation of genomic results to identify true pathogenic variation is a highly labor-intensive process, in Aim 2 we will refine and apply methods for high throughput screening of FHS/JHS genomes in a manner that retains high sensitivity for the detection of detrimental variants in an additional 4,572 disease-associated Mendelian diseases (which will not be returned) while reducing the false discovery rate of variants that are determined to be benign. In Aim 3 we will review available phenotype data and compare documented and self- reported phenotypes to variant classification in participants who do, and do not, carry detrimental variants in all 4,631 Mendelian disease-associated genes. By comparing genotype and phenotype data, we will refine a new method of estimating crude measures of aggregate penetrance and lay the groundwork for generating more refined penetrance estimates in larger sample sizes.