Genetics of human renal hypodysplasia

肾发育不良(RHD)是一种先天性肾脏畸形，常与 其他畸形和临床并发症。总体而言，肾脏和尿路 畸形的主要并发症是终末期肾功能衰竭(ESRD)，它们占高达 全世界50%的儿童和7%的成人ESRD。风湿性心脏病的生物学基础很差 明白了。目前已知基因中的罕见变异(单核苷酸变异和小核苷酸变异 插入删除变异体(SNV)和罕见拷贝数变异体(CNV)只能解释 导致10-20%的风湿性心脏病，限制了最佳诊断和预后工具的开发。 有趣的是，我们的初步数据表明，常见的变异与 肾脏和尿路畸形，指出了另一种机制来解决 风湿性心脏病的遗传性缺失。这个应用程序的中心假设是 遗传学方法可以促进我们对风湿性心脏病生物学基础的理解。这个 应用程序的基本原理是所有类型的遗传变异(常见和罕见的SNV 和CNV，从头开始和遗传)可导致风湿性心脏病，一些共病 与风湿性心脏病相关的基因有助于识别与综合征性风湿性心脏病相关的新基因。为了确保 作为一个全面的分析，我们将追求三个目标：1)正如已知的从头开始的变体 发育障碍的一个重要机制，我们将分析所有类型的负担 新变异体(SNV、CNV和非编码变异体)。2)既继承又继承 Novo突变导致风湿性心脏病并对其他疾病的发展具有多效性作用 在器官方面，我们也将采用病例对照方法。为了增强我们的统计能力，我们届时将 结合病例对照分析的结果和从头分析的结果， 并利用大量可公开获得的风湿性心脏病患者测序队列 进行合并病例对照分析。3)我们将测试是否常见 变异可以通过对一个基因进行全基因组关联分析来增加风湿性心脏病的风险 大量病例和对照，并计算多基因风险分数以预测风湿性心脏病(RHD- Prs)。然后我们将分析RHD-PR与其共病之间的关联，以及 检测RHD-PRS是否能改变罕见致病变种的影响。已被占用 总之，这一应用程序将研究一系列等位基因频率的变异，以更好地 了解它们对疾病的多效性、外显性和临床严重性的贡献。这个 该项目受益于研究人员在人类遗传、风湿性心脏病病例的大量队列中的专业知识， 以及最近NIH X01计划对全基因组测序的支持。

Renal hypodysplasia (RHD) is a congenital malformation of the kidney often associated with additional malformations and clinical complications. Overall, kidney and urinary tract malformations main complication is end-stage kidney failure (ESRD), and they account for up to 50% of pediatric and 7% of adult ESRD worldwide. The biological basis of RHD is poorly understood. Currently rare variants in known genes (single nucleotide variants and small insertion deletion variants, or SNVs) and rare copy-number variants (CNVs) only explain the cause of 10-20% of RHD, limiting the development of optimal diagnostic and prognostic tools. Interestingly, our preliminary data suggest that common variants are significantly associated with kidney and urinary tract malformations, pointing to another mechanism to resolve the missing heritability of RHD. The central hypothesis of this application is that comprehensive genetic approaches can advance our understanding of the biological basis of RHD. The rationale underlying the application is that all types of genetic variants (common and rare, SNVs and CNVs, de novo and inherited) can cause RHD, and that some of the comorbidities associated with RHD can help identify novel genes associated with syndromic RHD. To ensure a comprehensive analysis, we will pursue three aims: 1) As de novo variants are known to be an important mechanism for developmental disorders, we will analyze the burden of all types of de novo variants (SNVs, CNVs and non-coding variants). 2) As both inherited and de novo mutations contribute to RHD and have pleiotropic effects on the development of other organs, we will also utilize case-control approach. To increase our statistical power, we will then combine the results from the case-control analysis with the results from the de novo analysis, and take advantage of the large publicly available sequenced cohorts of patients with RHD comorbidities to perform a combined case-control analysis. 3) We will test whether common variants can increase the risk for RHD by performing genome-wide association analysis on a large set of cases and controls, and calculating a polygenic risk score to predict RHD (RHD- PRS). We will then analyze the association between the RHD-PRS to its comorbidities, and examine whether the RHD-PRS can modify the effect of rare pathogenic variants. Taken together, this application will investigate variation across a range of allele frequencies, to better understand their contribution to pleiotropy, penetrance and clinical severity of disease. The project benefits from the researchers expertise in Human Genetic, large cohorts of RHD cases, and recent support from the NIH X01 program for whole genome sequencing.