Investigating the contribution of non-coding genetic variation to rare disorders

项目概要/摘要 基因检测正迅速成为医学的基石，为患有遗传病的患者提供靶向治疗。 常见和罕见的疾病，并赋予患者，家庭和社区知识， 他们的状况然而，尽管在过去十年中取得了重大进展， 临床全基因组测序，临床遗传学仍然在很大程度上限于研究不到1%的 基因组，外显子组。这种局限性被认为是临床基因组测序被认为是 在阐明大多数假定的患者的罪魁祸首致病变异方面失败， 接受测试的单基因疾病患者。据推测，这些患者中有很大一部分 携带致病性非编码变异，破坏已知的孟德尔遗传的基因调控结构， 基因，一类变异使用目前的测序方法照明不足。直接解决这个问题 限制需要对基因检测的执行和解释方式进行全面修订，如 这个提议。具体而言，该提案旨在通过以下方式克服人类遗传学的这一基本限制： 利用我们最近开发的一种新方法， 因此，它阐明了非编码遗传变异的功能影响， 局部染色质结构和基因调控模式-全表观基因组测序（WEGS）。使用 通过这种方法，我们计划直接测试这一假设，即罕见的非编码基因改变有助于 单基因疾病在目标1中，我们将使用WEGS方法来表征基因调控的影响， 非编码序列，结构和表观遗传学改变在健康个体以及患者已知 印记障碍这个目标的目的是建立WEGS的灵敏度和权力，以识别 遗传变异破坏局部染色质结构和基因调控模式，并改善我们的 了解非编码遗传变异的功能影响。在目标2中，我们将直接评估 通过将WEGS应用于患有单基因疾病的患者， 疑似单基因疾病，其整个外显子组或基因组测序先前未被证实。 诊断总的来说，这项提议有可能极大地改变我们对基因组检测的态度。 以及我们对非编码序列和结构变异对基因调控的影响的理解， 模式和人类疾病。

PROJECT SUMMARY/ABSTRACT Genetic testing is rapidly emerging as a cornerstone of medicine, enabling targeted therapies for patients with both common and rare disorders, and empowering patients, families and communities with knowledge about their condition. However, despite significant advances over the past decade, including the introduction of clinical whole genome sequencing, clinical genetics remains largely limited to the study of less than 1% of the genome, the exome. This limitation is thought to underlie the fact that clinical genomic sequencing is unsuccessful in elucidating the culprit pathogenic variant(s) for the majority of patients with presumed monogenic disorders who undergo testing. It is hypothesized that a significant percentage of these patients harbor pathogenic non-coding variants that disrupt the gene regulatory architecture of known Mendelian genes, a class of variants poorly illuminated using current sequencing approaches. Directly addressing this limitation requires a wholesale revision of how genetic testing is performed and interpreted, as is outlined in this proposal. Specifically, this proposal aims to overcome this fundamental limitation of human genetics by leveraging a novel approach we recently developed for simultaneously mapping the genetic and epigenetic landscape of a sample, thereby illuminating the functional impact of non-coding genetic variants that disrupt local chromatin architecture and gene regulatory patterns – Whole Epi-Genome Sequencing (WEGS). Using this approach, we plan to directly test the hypothesis that rare non-coding genetic alterations contribute to monogenic disorders. In Aim 1, we will use the WEGS approach to characterize the gene regulatory impact of non-coding sequence, structural and epigenetic alterations in healthy individuals as well as patients with known imprinting disorders. The goal of this aim is to establish the sensitivity and power of WEGS for identifying genetic variants that disrupt local chromatin architecture and gene regulatory patterns and improve our understanding of the functional impact of non-coding genetic variation. In Aim 2, we will directly evaluate the contribution of rare non-coding genetic alterations to monogenic disorders by applying WEGS to patients with suspected monogenic disorders for whom whole exome or genome sequencing has previously been non- diagnostic. Overall, this proposal has the potential to dramatically change how we approach genomic testing and our understanding of the impact of non-coding sequence and structural variation on gene regulatory patterns and human disease.