Cardiomyopathy Genomes Project

项目摘要 心肌病具有高度遗传性，心肌病根据心脏形态学分为两类： 主要形式为扩张型和肥厚型心肌病（分别为DCM和HCM）。在成人家庭中， 心肌病，最常见的遗传形式是常染色体显性遗传，表现可变， 外显率基因检测现在采样超过80个基因，并在大约一半的基因中识别出主要突变 那些案子对于相同的单一突变，存在相当大的表型变异性。这一点在 家族，其中所有成员共享相同的主要突变，但具有不同的发病年龄和表达。 心肌病的“缺失遗传性”可能是由于多种因素，未发现的原发性或“驱动因素” 基因突变和/或涉及驱动变体之间相互作用的寡基因遗传机制， 它们表达的基因组背景。心肌病的基因组背景包括遗传 修饰符，其不限于基因组的编码区，并且可能包括非编码遗传修饰符。 变化量遗传修饰剂被定义为改变原发性肿瘤表型表达的遗传变体。 突变，并确定这些途径是有用的临床预后，并确定潜在的途径 可以围绕它进行治疗。从历史上看，心肌病遗传学研究一直是 仅限于基因组的一小部分， 失败全基因组测序（WGS）提供了更全面的基因组背景图片， 包括罕见和常见的变异，这些变异形成了驾驶员变异的表现形式， 编码区。在之前的资助期间，我们生成并分析了WGS数据， 来自>300名心肌病患者的心脏表型信息。作为补充，我们现在也 拥有来自西北大学NUgene生物库的>1000个个体的WGS数据，这些数据与 临床数据。心肌病基因组分析揭示了调节心脏能量学的基因变异 和线粒体功能作为HCM和DCM的修饰剂，因为我们将通过机制研究这一点。 模型生物和人类细胞模型的方法。我们现在打算破译复杂的 通过整合WGS信息、表观遗传标记和基因表达数据，研究心肌病遗传学。 定义心肌病的遗传修饰剂有望提供新的途径， 失败

PROJECT SUMMARY Cardiomyopathy is highly heritable, and cardiomyopathies are classified based on heart morphology with two major forms being dilated and hypertrophic cardiomyopathy (DCM and HCM, respectively). In adult familial cardiomyopathy, the most common form of inheritance is autosomal dominant with variable expressivity and penetrance. Genetic testing now samples >80 genes and identifies a primary mutation in approximately half the cases. With the same single mutation, there is considerable phenotypic variability. This is well seen in families, where all members share the same primary mutation but with differing age of onset and expression. The “missing heritability” for cardiomyopathy may be due to multiple factors, undiscovered primary or “driver” gene mutations and/or an oligogenic genetic mechanism involving the interplay between driver variants and the genomic context in which they are expressed. The genomic context for cardiomyopathy includes genetic modifiers, which are not restricted to coding regions of the genome and likely includes noncoding genetic variation. Genetic modifiers are defined as genetic variants that alter the phenotypic expression of a primary mutation, and identifying these pathways is useful for clinical prognosis and to identify potential pathways around which therapy can be developed. Historically, cardiomyopathy genetic investigations have been restricted to a small fraction of the genome with limited information on the larger genomic signature of heart failure. Whole genome sequencing (WGS) provides a more comprehensive picture of genomic context, including both rare and common variation, that shapes the manifestation of driver variant(s) extending beyond the coding region. In the prior funding interval, we generated and analyzed WGS data coupled with clinical cardiac phenotype information from >300 individuals with cardiomyopathy. As a complement, we also now have WGS data from >1000 individuals from Northwestern's NUgene Biobank, and these data are linked to clinical data. Analysis of the cardiomyopathy genomes reveals variants in genes regulating cardiac energetics and mitochondrial function as modifiers of HCM and DCM, as we will study this through mechanistic approaches in model organisms and human cell models. We now propose to decipher complex cardiomyopathy genetics by integrating WGS information, epigenetic signatures, and gene expression data. Defining genetic modifiers for cardiomyopathy is expected to provide novel pathways contributing to heart failure.