Cardiomyopathy Genomes Project

项目总结 心肌病是高度遗传性的，心肌病根据心脏形态分为两类 主要形式为扩张型和肥厚型心肌病(分别为扩张型和肥厚型)。在成人家族中 心肌病，最常见的遗传形式是常染色体显性遗传，具有可变的表现性和 洞察力。基因检测现在对&gt；80个基因进行采样，并在大约一半的基因中发现一个主要突变 这些案子。对于相同的单一突变，有相当大的表型变异。这一点在 所有成员都有相同的主要突变，但发病年龄和表现不同的家族。 心肌病的“遗漏遗传性”可能是由于多种因素，未发现的原发因素或“驱动因素” 基因突变和/或涉及驱动变异体和 表达它们的基因组环境。心肌病的基因组背景包括遗传 修饰物，不限于基因组的编码区，可能包括非编码遗传 变种。遗传修饰物被定义为改变初级基因表型表达的遗传变体 突变，识别这些途径对临床预后和识别潜在途径是有用的 围绕着它可以开发出治疗方法。从历史上看，心肌病基因研究一直是 仅限于基因组的一小部分，关于心脏较大基因组签名的信息有限 失败了。全基因组测序(WGS)提供了基因组背景的更全面的图景， 包括罕见和常见的变异，这塑造了司机变异(S)延伸到更远的表现 编码区。在之前的资助周期中，我们生成并分析了WGS数据和临床数据 来自&gt；300名心肌病患者的心脏表型信息。作为补充，我们现在也 有来自西北大学Nugene生物库的1000人的WGS数据，这些数据链接到 临床数据。对心肌病基因组的分析揭示了调控心脏能量学的基因的变异 和线粒体作为HCM和DCM的修饰物，因为我们将通过机械学来研究这一点 模式生物和人体细胞模型中的方法。我们现在建议破译复杂的 整合WGS信息、表观遗传学特征和基因表达数据的心肌病遗传学研究。 定义心肌病的遗传修饰物有望提供有助于心脏的新途径 失败了。

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.