ADPKD: Disease Spectrum & Genotype-Phenotype Correlations

描述（由申请方提供）：常染色体显性多囊肾病（ADPKD）是最常见的单基因疾病之一（1：400 - 1000），也是终末期肾病（ESRD）的重要原因。2012年在美国，约30，000例PKD相关ESRD患者; 1/3500例65 - 69岁的患者。该疾病通常发病较晚，但存在相当大的变异性，从子宫内发病和围产期死亡，早发（EO）疾病， 直到老年才有足够的肾功能。肾外表现，特别是颅内动脉瘤（ICA）和严重多囊肝病（sPLD）的发生率较高，与发病率和死亡率相关。该提案的总体目标是确定两个已知基因PKD 1（16 p13.3）和PKD 2（4q21）以及基因组其他地方的遗传因素在多大程度上决定肾脏疾病的严重程度和临床上显着的肾外并发症的发生。这些研究是基于我们的发现，以及其他人的发现，即基因，等位基因和遗传背景效应显着影响表型。下一代测序（NGS）将用于ADPKD基因（包括重复PKD 1）的突变筛查，需要通过基因座特异性长距离PCR（LR-PCR）进行富集。基因组中其他地方的突变和变异将采用定制的候选基因组（Haloplasty方法）和全外显子组测序（WES）进行鉴定。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的作用，特别是引起EO疾病。目的2将分析一个大的，典型的ADPKD人群和血管和sPLD表型的人，以确定ADPKD基因和等位基因效应在占表型变异的全部作用。目的3将筛选ADPKD基因以外的位点，包括整个外显子组，以寻找导致ADPKD样表型的新致病基因。目的4将分析导致EO疾病和临床显著的血管和肝脏并发症的修饰因子的整个外显子组。最终的目标将是在体内测试推定的致病ADPKD等位基因的意义，分析发病机制，并优化用于临床前测试的小鼠模型。总的来说，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，优化临床前测试模型，具有诊断和预后价值，并确定适合临床试验的人群，并将获得最多的疾病特异性治疗药物，这些药物将很快上市。

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.