Genetic Signals in Ventricular Hypertrophy

描述（由申请人提供）：左心室质量增加或肥大（LVH）是心血管事件的独立危险因素。遗传变异，最常见于编码肌节蛋白组分的基因，是导致肥厚型心肌病（HCM）的LVH的重要主要原因。HCM患者的遗传学研究确定了50-60%的成人型家族性HCM、~30%的成人型散发性HCM和~40%的儿童型HCM的致病性突变。在约50%的成人和儿童中，特别是在那些没有家族性疾病的人中，临床上表现为HCM的LVH的原因仍然未知。为了解决这一知识缺口，我们将在没有公认的遗传病因的肥大受试者中进行基因组DNA和心脏组织RNA的综合分析。我们将通过基于测序的策略在细胞核和线粒体基因组中寻找未检测到的种系和体细胞变异，并将考虑致病性病因（目标1）。为了评估新序列变体和基因的致病性，我们将建立在现有的RNAseq数据集上，以确定候选基因是否参与肥大信号通路，我们使用高通量策略来调节小鼠中的候选基因表达并进行详细的心脏分析（目的2）。大约10%的普通人群携带罕见的肌节蛋白基因的非同义变体，而不发展明显的HCM。为了理解基因型和表型的不一致性，我们将在肌丝蛋白的3-D结构上绘制罕见的非同义的、确定的家族性HCM突变和群体鉴定的肌节变体，并评估它们在源自分化的同基因iPS细胞的肌细胞中的功能（Aim 3）。总的来说，这些研究将扩大HCM和LVH的遗传和获得性原因的库，并提高对罕见遗传变异引起的表型的准确预测。我们的目标是：1）使用高通量DNA测序方法评估LVH患者心脏组织和基因组的遗传变异。2)证明新的分子在体内引起或改变LVH。3)定义在普通人群中发现的罕见人类肌节蛋白基因变异的致病性。

DESCRIPTION (provided by applicant): Increased left ventricular mass or hypertrophy (LVH) is an independent risk factor for cardiovascular events. Genetic variation, most commonly in genes encoding the protein constituents of the sarcomere, is an important primary cause of LVH that results in hypertrophic cardiomyopathy (HCM). Genetic studies of HCM patients identify pathogenic mutations in 50-60% of adult-onset familial HCM, ~30% of adult-onset sporadic HCM and ~40% of pediatric-onset HCM. Causes of LVH that clinically presents as HCM in ~50% of adults and children, particularly in those without familial disease, remains unknown. To address this gap in knowledge, we will perform integrated analyses of genomic DNA and cardiac tissue RNA in hypertrophic subjects without a recognized genetic etiology. We will search for undetected germline and somatic variants in the nuclear and mitochondrial genomes through sequenced-based strategies and will consider pathogenic etiologies (Aim 1). To assess the pathogenicity of novel sequence variants and genes we will build upon existing RNAseq datasets to determine if candidate genes participate in hypertrophic signaling pathways and we use high-throughput strategies to modulate candidate gene expression in mice and perform detailed cardiac analyses (Aim 2). Approximately 10% of the general population carries rare non- synonymous variants in sarcomere protein genes without developing overt HCM. To understand discordance in genotype and phenotype, we will map rare non-synonymous, definitive familial HCM mutations and population-identified sarcomere variants on 3-D structures of myofilament proteins, and assess their function in myocytes derived from differentiated isogenic iPS cells (Aim 3). Collectively these studies will expand the repertoire of genetic and acquired causes of HCM and LVH and improve the accurate prediction of phenotypes that arise from rare genetic variation. Our aims will: 1) Assess genetic variation in cardiac tissue and genomes of patients with LVH using high-throughput DNA sequencing methods. 2) Demonstrate that novel molecules cause or modify LVH in vivo. 3) Define the pathogenicity of rare human sarcomere protein gene variants found in the general population.