ADPKD: Disease Spectrum & Genotype-Phenotype Correlations

描述(申请人提供)：常染色体显性遗传性多囊肾病(ADPKD)是最常见的单基因疾病之一(1：400-1000)，是终末期肾脏疾病(ESRD)的重要原因。2012年，在美国，约30,000名患者患有PKD相关的ESRD；65-69岁的人中有1/3500人患有PKD。这种疾病通常发病较晚，但存在相当大的变异性，从宫内发病和围产期死亡，早发性(EO)疾病， 到老年时肾功能正常。肾外表现，尤其是颅内动脉瘤(ICA)和严重多囊肝病(SpLD)的发生率较高，与发病率和死亡率有关。这项建议的总体目标是确定两个已知基因PKD1(16p13.3)和PKD2(4q21)以及基因组其他地方的遗传因素在多大程度上决定了肾脏疾病的严重程度和临床上重要的肾外并发症的发生。这些研究是基于我们的发现，以及其他关于基因、等位基因和遗传背景效应显著影响表型的研究。下一代测序(NGS)将用于ADPKD基因的突变筛查，包括重复的PKD1，需要通过座位特异性长程聚合酶链式反应(LR-PCR)进行浓缩。基因组中其他地方的突变和变异将利用定制的候选基因小组(HaloPlex方法)和整个外显子组测序(WES)来识别。目的1将筛选ADPKD基因，以确定目前未解决的7%-10%患者中的非典型突变，并评估等位基因组合作为致病事件，特别是导致EO疾病的作用。目的2将分析大量典型的ADPKD人群和具有血管和SpLD表型的人群，以确定ADPKD基因和等位基因效应在解释表型变异中所起的全部作用。AIM 3将筛选ADPKD基因以外的基因座，包括整个外显子组，寻找导致ADPKD样表型的新致病基因。目的4将分析整个外显子组，以寻找导致EO疾病和临床上重要的血管和肝脏并发症的修饰因素。最终目的是检验可能致病的ADPKD等位基因在体内的意义，分析发病机制，并优化小鼠模型进行临床前试验。总体而言，这些研究将更好地解释ADPKD的遗传原因，提供对发病机制的见解，可能揭示新的治疗靶点，优化临床前测试的模型，具有诊断和预后价值，并确定适合临床试验的人群，这些人群将从即将推出的疾病特异性疗法中获得最多。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders (1:400-1000) and an important cause of end stage renal disease (ESRD). In the US in 2012, ~30,000 patients had PKD associated ESRD; 1/3500 individuals aged 65-69y. The disease is generally late in onset, but considerable variability exists, from in utero onset and perinatal death, early onset (EO) disease, to adequate renal function into old age. Extrarenal manifestations, particularly a higher incidence of intracranial aneurysms (ICA) and severe polycystic liver disease (sPLD) are associated with morbidity and mortality. The overall goal of this proposal is to determine the extent to which genetic factors at the two known genes, PKD1 (16p13.3) and PKD2 (4q21) and elsewhere in the genome, determine the severity of renal disease and the occurrence of clinically significant extrarenal complications. These studies are based upon our findings, and those of others that genic, allelic and genetic background effects significantly influence the phenotype. Next generation sequencing (NGS) will be employed for mutation screening of the ADPKD genes, including the duplicated PKD1, necessitating enrichment by locus specific long-range PCR (LR-PCR). Mutations and variants elsewhere in the genome will be identified employing custom-made panels of candidate genes (HaloPlex methodology) and whole exome sequencing (WES). Aim 1 will screen the ADPKD genes to identify atypical mutations in the 7-10% of patients that are presently unresolved, and assess the role of allelic combinations as pathogenic events, especially causing EO disease. Aim 2 will analyze a large, typical ADPKD population and ones with the vascular and sPLD phenotype to determine the full role that ADPKD genic and allelic effects play in accounting for phenotypic variability. Aim 3 will screen loci beyond the ADPKD genes, including the whole exome, for novel causative genes resulting in an ADPKD-like phenotype. Aim 4 will analyze the whole exome for modifying factors that cause EO disease and clinically significant vascular and hepatic complications. The final aim will test the significance of putative pathogenic ADPKD alleles in vivo, analyzing the mechanisms of pathogenesis and optimizing mouse models for preclinical testing. Overall these studies will better explain the genetic causes of ADPKD, provide insights into the pathogenesis, possibly revealing novel therapeutic targets, optimize models for preclinical testing, be of diagnostic and prognostic value, and identify populations suitable for clinical trials and that will gain most fro disease-specific therapeutics which will be available soon.