Center for Undiagnosed Pediatric Renal and Urogenital Disorders

描述（由申请人提供）：肾脏和泌尿生殖系统疾病是一种主要的健康负担，人们对其知之甚少，并且通常在临床上难以治疗。同样重要的是，这些器官的解剖缺陷往往与严重的、危及生命的系统性综合征有关，这些综合征在诊断时可能仍然是屈光性的。我们中心的使命是将尖端的基因组学工具和解释性生物学分析结合起来，以加强和加速这些疾病的分子诊断。我们提出了三个主要活动：a)从杜克大学诊所招募的家庭中提取表型、招募和生物样本，同时也从美国各地转介给我们的先天性解剖性肾脏和泌尿生殖缺陷患者，这些患者未能通过传统手段获得分子诊断；B)对合适的家庭成员进行外显子组（最终是基因组）测序；C)对已发现的具有预测临床价值的变异子集进行功能测试，并开发体外（原代细胞）和体内工具（斑马鱼和小鼠）来模拟这种变异的影响；D)综合混合临床和研究数据，与临床管理团队合作，为未来的患者管理和干预提供信息。同时，我们提出两项高风险的试点活动，旨在改善

DESCRIPTION (provided by applicant): Disorders of the renal and urogenital system represent a major health burden, remain poorly understood, and are often clinically intractable. Of equal importance, anatomical defects in these organs are associated frequently with serious, life-threatening systemic syndromes that can remain refractive to diagnosis. The mission of our Center is to bring together cutting-edge genomics tools and interpretative biological assays to potentiate and accelerate the molecular diagnosis of these disorders. We propose three major activities: a) to phenotype, recruit and biobank samples from families recruited at the Duke clinics but also referred to us from across the United States with congenital anatomical renal and urogenital defects that have failed to secure a molecular diagnosis through traditional means; b) to perform exome (and ultimately genome) sequencing on appropriate family members; c) to functionally test a subset of discovered variation that is of predicted clinical value and to develop in vitro (primary cells) and in vivo tools (zebrafish and mouse) to model the effects of such variation; d) to synthesize hybrid clinical and research data that, in collaboration with the clinical management team, can inform future management and intervention in patients. In parallel, we propose two high-risk pilot activities aimed at improving both the genetics and the discovery of novel therapeutic leads. First, we will develop the technology for the rapid identification of new zebrafish renal mutants that can accelerate the identification of new genes important in kidney development. Second, we will generate new platforms for the screening of lead compounds in zebrafish models of renal disease (both previously established and newly-developed as part of our Center). Finally, because our Center represents a collaboration between patients, physicians and basic scientists, we will develop information platforms to facilitate the dissemination of exome-wide research and clinical data to both physicians and patient families, and to learn iteratively from this community about how to best implement such information to improve health care. Taken together, our Center will provide a much-needed niche in the field, will likely improve the knowledge base of both physicians and patients about syndromes with a renal and urogenital component, and will provide the foundation for accelerated diagnosis, management and treatment.