Characterizing disease-causing variants using personal genomes with large recurrent deletions

摘要 基因组精确医学领域的一个主要挑战是观察到基因并不总是 预测孟德尔疾病的表型。这种表型差异被认为部分是由共同的 变异体和变异体具有微妙的影响，但这些修饰等位基因的潜在决定性作用没有 在临床环境中被严格或系统地研究过。朝着破译黑洞的长期目标前进 人类单基因疾病不完全外显和表现力变异的遗传基础 旨在研究具有相同基因组重排的复发性基因组疾病患者 以不完全渗透的方式表现疾病表型。这一拟议项目的总体目标是 制定一种可推广的方法，使用复发性大基因组缺失患者队列，可以 识别和表征具有临床意义的疾病修饰变异体。中心假设是患者 反复发生的大基因组缺失为识别疾病修饰提供了有效的基因组背景 作为个体患者疾病结局的可靠预测因子的等位基因。这一中心假设将是 通过定义两个基因组座位上特定表型表现的遗传决定因素进行测试：早期 17q12出现糖尿病，1q21.1出现头部大小异常。将聚集大规模的患者资源 基于临床诊断学提供的分子信息。招募的患者将在以下地点进行分析 通过全基因组测序从分子水平进行分析。将进行表型-基因相关分析 根据以下初步数据确定不同疾病修改模式下的候选修饰等位基因 每种疾病的病源地。选定的疾病修改等位基因的功能验证将使用患者- 衍生的诱导多能干细胞。本研究的创新之处在于组装了稀有的个人 来自临床诊断数据库的具有相同拷贝数变体的基因组使人类受试者能够 “增强器屏幕。”这项拟议的研究具有重要意义，因为它有望确定临床上重要的 存在或不存在重复缺失基因座的等位基因可用于准确的诊断、咨询和 遗传性疾病患者的管理。这里使用的研究策略可以概括为 其他表型或基因组基因座，以及已发现的一般机制将直接适用于 理解人类疾病中的不完全外显和可变表现力。

Abstract A major challenge in the field of genomic precision medicine is the observation that genotype does not always predict phenotype in Mendelian disorders. This phenotype variation is thought to be caused in part by common variants and variants with subtle effects, but the potential deterministic roles of such modifier alleles have not been rigorously or systematically studied in clinical settings. Toward the long-term goal of deciphering the genetic basis of incomplete penetrance and variable expressivity in human monogenic diseases, this proposal aims to study patients with recurrent genomic disorders in whom identical genomic rearrangements manifest disease phenotypes in an incompletely penetrant manner. The overall objective of this proposed project is to formulate a generalizable approach using cohorts of patients with recurrent large genomic deletions that can identify and characterize clinically significant disease-modifying variants. The central hypothesis is that patients with recurrent large genomic deletions offer an effective genomic background to identify disease-modifying alleles that serve as reliable predictors of disease outcome in individual patients. This central hypothesis will be tested by defining the genetic determinants of specific phenotype presentations at two genomic loci: early onset diabetes at 17q12 and abnormal head size at 1q21.1. Large-scale patient resources will be gathered based on molecular information made available by clinical diagnostics. Recruited patients will be analyzed at the molecular level by whole genome sequencing. Phenotype–genotype correlation analysis will be performed to identify candidate modifier alleles under different disease-modifying models based on preliminary data from each disease locus. Functional validation of selected disease-modifying alleles will be performed using patient- derived induced pluripotent stem cells. The innovation of this study lies in the assembly of rare personal genomes with identical copy number variants from clinical diagnostic databases to enable a human subject “enhancer screen.” The proposed research is significant because it is expected to identify clinically important alleles in recurrent deletion loci whose presence or absence can be used for precise diagnosis, counseling and management for patients with genetic disorders. The research strategy utilized herein could be generalized to other phenotypes or genomic loci, and the general mechanisms discovered will be directly applicable to understanding incomplete penetrance and variable expressivity in human diseases.