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

点击翻译按钮获取中文摘要

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.