Identification of CAKUT-associated genes using a worldwide patient-cohort and high-throughput methods for genetic analysis

先天性肾脏和泌尿道异常（CAKUT）包括一个大范围的病理条件。CAKUT在生命的前二十年中导致50%的终末期肾脏疾病，并且通常需要长期进行成本密集型肾脏替代治疗。CAKUT目前被认为主要是基于受影响者DNA的异常而发展的。然而，直到今天，只有一小部分疾病相关基因已被成功地确定和功能特征。Hildebrandt博士（HHMI，波士顿儿童医院，哈佛医学院）在他的实验室中建立了一种有效鉴定CAKUT相关基因的诊断方法。在接下来的几年中，申请人计划将这些用于遗传分析的高通量方法（例如纯合性作图、全外显子组测序）应用于他现有的全球2，400个CAKUT家族的队列。此外，申请方将利用这些方法分析由近150例肛门直肠畸形和相关CAKUT患者组成的自身队列的DNA。从长远来看，有希望成功识别越来越多的CAKUT基因可以有助于更好地了解疾病相关的分子途径和CAKUT的病理生理学。

Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT) comprise a large spectrum of pathological conditions. CAKUT contribute to 50% of terminal kidney diseases during the first two decades of life and often necessitate cost-intensive kidney-replacement-therapies in the long term. CAKUT are currently believed to develop predominantly based on abnormalities in the DNA of the affected. However, until today only a small fraction of disease-related genes has successfully been identified and functionally characterized. Dr. Hildebrandt (HHMI, Boston Childrens Hospital, Harvard Medical School) has established a diagnostic approach for the efficient identification of CAKUT-associated genes in his laboratory. Throughout the next few years, the applicant is planning to apply these high-throughput methods for genetic analysis (e.g. homozygosity mapping, whole exome sequencing) to his existing, world-wide cohort of 2,400 families with CAKUT. The applicant will furthermore utilize the methods to analyze the DNA of an own cohort consisting of nearly 150 patients with anorectal malformations and associated CAKUT. In the long term, there is hope that a successful identification of an increasing number of CAKUT-genes can contribute to a better understanding of disease-associated molecular pathways and the pathophysiology of CAKUT overall.