Genetic diagnosis of kidney and urinary tract malformations via copy number varia

描述（由申请人提供）：先天性肾脏和尿路异常（先天性肾脏和尿路异常）占全球儿童终末期肾衰竭的40-50%。CAKUT可以作为家族性或散发性疾病发生，具有高度可变的表型表达。在过去的40年里，CAKUT的诊断方法依赖于对解剖缺陷的描述，这种描述很难区分疾病的亚型，并且提供的预后信息很少。由于缺乏对主要发病机制的基本认识，治疗选择也受到严重限制。我们发现，近20%的肾发育不良/发育不全患者被诊断为已知或新的基因组疾病，这在诊断、遗传咨询和发生严重肾外表现（如自闭症、智力低下等）的风险分层方面具有重要意义。在这里，我们建议将我们的研究扩展到600名CAKUT患者，以鉴定致病性亚显微结构变异，并在实验室中已经进行基因分型的400名患者中验证我们的结果，并在合作者和费城儿童医院（CHOP）进行基因分型的1000名患者中重复结果。此外，我们将继续鉴定较小的、潜在致病性的单基因CNVs，并将通过筛选家族性和散发性患者中的独立点突变来追踪结果，以鉴定新的cakut特异性基因。我们将及时与研究界分享数据，以促进该领域的进展。

DESCRIPTION (provided by applicant): Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for 40-50% of pediatric end-stage kidney failure worldwide. CAKUT can occur as familial or sporadic disease with highly variable phenotypic expression. For the past 40 years, the diagnostic approach to CAKUT has relied on description of anatomic defects, which poorly discriminates subtypes of disease and provides little prognostic information. Due to paucity of fundamental insight about primary pathogenesis, therapeutic options are also severely limited. We showed that almost 20% of patients with renal hypodysplasia/agenesis carry a diagnosis of a known or novel genomic disorder, with important implications in diagnosis, genetic counseling and stratification of risk for developing severe extra-renal manifestations, such as autism, mental retardation, and others. Here, we propose to extend our study to 600 CAKUT patients for the identification of pathogenic sub- microscopic structural variants and to validate our results in 400 patients already genotyped in the lab, and replicate results in 1,000 patients genotyped by collaborators and the Children's Hospital of Philadelphia (CHOP). Moreover, we will proceed to identify smaller, potentially pathogenic single-gene CNVs and we will follow up the results by screening for independent point mutations in familial and sporadic patients to identify novel CAKUT-specific genes. We will share data promptly with the research community to aid progress in the field.