CNV Atlas of Human Development

描述（由申请人提供）：最近发现拷贝数变异（CNVs），即小基因组片段的丢失或获得，在所有正常个体中都很常见，并且在人类表型变异和疾病中起着重要作用，对我们对人类遗传变异的理解产生了深远的影响。然而，我们预测哪些CNVs具有生物学或健康意义的能力严重有限；从多个正常人群和患者人群中获取更全面和准确的CNV数据是一项紧迫的研究和公共卫生重点。高分辨率CNV评估的强大技术现已可用，并已进入临床诊断用途，用于评估患有不明原因的智力残疾、自闭症或多重出生缺陷的儿童（称为“分子核型”或细胞基因组阵列）。目前的多中心试验也在进行中，以确定这些技术在产前诊断中的功效。很有可能在未来几年内，细胞基因组阵列将成为儿科和产前细胞遗传学分析的首选方法。临床细胞遗传学实验室正在进行的大量细胞基因组阵列测试提供了一个不寻常且及时的机会，可以从患者群体中获取大量数据集，从而有助于我们了解临床人群与正常人群相比CNVs的后果。该项目的总体目标是利用临床护理过程中产生的大型临床数据集，为发现与人类发育障碍相关的基因创造研究资源，并为了解CNVs的临床和公共卫生影响建立宝贵的临床资源。该项目将包括四个具体目标：1)从儿科和产前人群的临床阵列测试中收集非常大的标准化数据集。除了传统的完全知情同意模型之外，我们还将使用一种新颖的“选择退出”同意机制，为大型临床站点和临床遗传学测试实验室开发方法，以收集CNV和临床数据并将其提交到中央公共数据存储库。2)规范临床实验室阵列设计和基因型（CNV）数据格式。与国际标准细胞基因组阵列（ISCA）联盟合作，我们正在制定阵列设计、分辨率、格式和良性与致病性CNVs解释指南的标准。3)建立标准化的临床（表型）数据。表型工作组将根据目前的国际建议制定表型信息的标准词汇表和数据字典。4)数据收集/存储，管理和可视化工具开发。数据库工作组将监督软件桥接和适配器的开发，以自动化数据去识别、重新格式化并传输到中央公共存储库（dbGaP、NCBI）。在为研究界和临床医生公开发布之前，将开发自动化和专家数据管理的方法。将与学术团体和商业供应商合作开发便于使用的数据可视化和分析工具。

DESCRIPTION (provided by applicant): The recent discovery that copy number variations (CNVs), the loss or gain of small genomic segments, is common in all normal individuals and plays a major role in human phenotypic variation and disease, has had a profound impact on our understanding of human genetic variation. However, our ability to predict which CNVs have biological or health significance is severely limited; the acquisition of more comprehensive and accurate CNV data from multiple normal and patient populations is an urgent research and public health priority. Powerful technologies for high-resolution CNV assessment are now available and have moved into clinical diagnostic use to evaluate children with unexplained intellectual disabilities, autism, or multiple birth defects (termed "molecular karyotypes" or cytogenomic arrays). Current multicenter trials are also underway to determine the efficacy of these technologies for prenatal diagnosis. It is very likely that cytogenomic arrays will become the method of choice for both pediatric and prenatal cytogenetic analysis within the next few years. The large number of cytogenomic array tests now being performed by clinical cytogenetics laboratories presents an unusual and timely opportunity to capture large datasets from patient populations to contribute to our understanding of the consequence of CNVs from clinical populations compared to normal populations. The overall goal of this project is to leverage this large clinical dataset generated in the course of clinical care to create a research resource for gene discovery related to human developmental disorders as well as to build an invaluable clinical resource for learning about the clinical and public health impact of CNVs. This project will encompass four specific aims: 1) Collection of very large standardized datasets from clinical array testing in pediatric and prenatal populations. Using a novel "opt-out" consent mechanism in addition to a traditional full informed consent model, we will develop methods for a large consortium of clinical sites and clinical genetics testing laboratories to collect and submit CNV and clinical data to a central, public data repository. 2) Standardize array design and genotype (CNV) data formats for clinical laboratories. In partnership with the International Standard Cytogenomic Array (ISCA) Consortium, we are developing standards for array design, resolution, format, and guidelines for interpretation of benign versus pathogenic CNVs. 3) Develop standardized clinical (phenotype) data. A Phenotype Workgroup will develop standard vocabularies and data dictionaries for phenotypic information using current international recommendations. 4) Data collection/repository, curation and visualization tool development. A database workgroup will oversee development of software bridges and adaptors to automate data de-identification, reformatting and transfer to a central public repository (dbGaP, NCBI). Methods for automated and expert data curation will be developed prior to public release for the research community as well as clinicians. User-friendly tools for data visualization and analysis will be developed in partnership with academic groups and commercial vendors. PUBLIC HEALTH RELEVANCE: The loss or gain of small regions in our genome, Copy Number Variations (CNVs), have recently been recognized as a major cause of both common and rare human diseases with enormous potential public health impact. Our current understanding of CNVs is limited: some are truly benign, some are thought to be benign but may in the future be shown to be associated with common diseases, and others are associated with disease and can provide important information for patients and families. To better understand CNVs, we propose a unique strategy to obtain high-quality, standardized data on CNVs linked to clinical information from very large populations (hundreds of thousands) during the course of routine clinical care in a prenatal and pediatric setting at minimal cost.