Research Project 1

肾脏和泌尿生殖道的疾病占解剖学缺陷的很大一部分 这对新生儿和幼儿构成重大负担，对家庭和医疗保健系统构成重大负担。他们 需要多种医学干预，有时还需要外科干预；它们通常仍然是模糊的分子 病因学；并可能是复杂的、综合征的、有时危及生命的疾病的先兆 表现在儿童和青春期的后期。基因组技术的最新进展提供了一种独特的 有机会研究这些疾病，并提供准确和及时的诊断，在某些情况下，将 帮助集中和/或调整医疗保健方向，并向有受影响儿童的家庭提供支持。 此外，这种遗传方法特别有吸引力，因为过去的研究通常是大规模的 家族或广泛的队列，导致了高渗透性突变的鉴定，这反过来又 阐明了疾病的发病机制。项目1旨在利用公爵的广泛基础设施 儿科和新生儿诊所建立一种我们可以有效利用信息的方法 从基因组研究中获得改善临床评估和后续治疗的儿童 肾脏和泌尿生殖道畸形。此外，这项研究的数据可能有助于了解 控制生殖道发育的细胞机制，并通过传播我们的 整个中心和科学界的发现，加强了一系列新的研究，从基础 生物学促进了新的治疗模式的发展。我们提出了两个目标。首先，我们将确定和 对50名患有综合征和非综合症儿童的初始队列进行详细的表型鉴定 肾脏和尿路的综合征先天畸形及其父母。第二，我们将 执行完整的外显子组测序以识别潜在的致病变异并开发最佳实践 用于返回临床确认的突变数据以及混合的临床和研究研究 给医生足够的信心。这些研究将使整个外显子组测序在 为我们的中心和更广泛的社区设置临床环境并加强丰富的研究发现 相关性(请参阅说明)： 先天性肾脏和泌尿生殖系统疾病极大地增加了婴儿发病率和死亡率， 尽管已知它们部分是由穿透性突变引起的，但大多数患者 有这种表型的人从来没有接受过分子诊断。项目1将寻求实施尖端技术 基因组技术，以改善这种诊断和结果，并加强生物发现。

Disorders of the kidney and urogenital tract represent a substantial fraction of anatomical defects in neonates and young children and pose a significant burden in families and the healthcare system. They require multiple medical, and sometimes surgical, interventions; they typically remain of obscure molecular etiology; and can be the harbinger of complex, syndromic, sometimes life-threatening conditions that manifest later in childhood and adolescence. Recent advances in genomic technologies offer a unique opportunity to study these disorders and to offer accurate and timely diagnosis that, in some instances, will help focus and/or redirect medical care, as well as provide support to families with affected children. Moreover, such genetic approaches are particularly attractive because past studies, typically on large families or extensive cohorts, have led to the identification of highly penetrant mutations, which have In turn illuminated disease pathomechanism. Project 1 aims to leverage the extensive infrastructure at the Duke Pediatric and Neonatal Clinics to establish a method by which we can utilize efficiently the information obtained from genomic studies to improve clinical evaluation and subsequent treatment of children with kidney and urogenital tract malformations. In addition, data from this study have the potential to help inform the cellular mechanisms governing genitourinary tract development and, through the dissemination of our findings both across this Center and to the scientific community, potentiate a range of new studies from basic biology to the development of new therapeutic paradigms. We propose two Aims. First, we will ascertain and perform detailed phenotypic characterization of an initial cohort of 50 children with syndromic and non- syndromic congenital anomalies of the kidney and the urinary tract and their parents. Second, we will perform whole exome sequencing to identify potential disease causing variants and to develop best practices for the return of both clinically-confirmed mutational data as well as hybrid clinical and research studies of sufficient confidence to physicians. These studies will inform the utility of whole exome sequencing in the clinical setting and potentiate rich research discovery for our Center and the broader community RELEVANCE (See instructions): Congenital renal and urogenital disorders contribute significantly to infant morbidity and mortality, and, despite the fact that they are known to be caused, in part, by penetrant mutations, the majority of patients with such phenotypes never receive molecular diagnoses. Project 1 will seek to implement cutting edge genomic technologies to improve such diagnoses and outcomes and to potentiate biological discovery.