Congenital anomalies of the kidney and urinary tract (CAKUT) represent highly understudied conditions, but have tremendous impact on patient morbidity and mortality. Among CAKUT categories, congenital obstructive uropathy (COU) represents a common and severe form of malformation. Recent technological improvements and advances in clinical testing have resulted in increased detection rates of congenital anomalies during pregnancy, but our ability to provide prognostication and care has lagged behind given limited ability to provide an etiological diagnosis and its associated risk for negative outcome in the postnatal life. In fact, depending on the severity and/or co-occurrence of other perturbations in development, COU can lead to significant morbidity and mortality after birth, and may require early surgical interventions to reduce the risk of progression to kidney failure. Despite medical and surgical management of urinary obstruction after birth, COU patients can rapidly progress to end-stage kidney disease (ESKD) requiring dialysis or transplantation and we are currently very limited in our ability to prognosticate this outcome. Moreover, a significant fraction of COU patients present with extra-urinary disease that is not detectable by standard prenatal imaging or clinical studies, but that impose significant added morbidity and mortality later in life. Our ability to provide adequate prenatal care, risk stratification, counselling and family planning, is again severely inadequate in this respect. Therefore, when facing with prenatal imaging of fetal anomalies, families are presented with limited options, which might include decision regarding termination of pregnancy. This is particularly sensitive because of its legislation, and often families with COU are left with difficult decisions to make. Genetics has the potential to aid in the ascertainment of diagnosis, prognosis and treatment of COU patients. However, genetic discoveries in COU lag behind when compared to other congenital anomalies due to small and heterogeneous cohorts that have been subjected to genetic testing until now. Here we propose a new comprehensive human genetic program designed to improve our understanding of the genetic basis of COU with a major final goal to improve risk stratification for urinary and extra-urinary disease, in order to facilitate family planning and counseling, prognosis, and, eventually, treatment. Specifically for this R56 mechanism, we will conduct the first GWAS for common variants in non-Mendelian COU.

PROJECT NARRATIVE Congenital obstructive uropathy is the most frequent anomaly of the urinary tract detected by prenatal ultrasound, occurring in up to 2% of normal pregnancies. Here we propose to study the human genetics of congenital obstructive uropathy and its subphenotypes using large-scale genetic screenings for rare and common variant in uniquely large and deeply phenotyped cohorts. This study will provide insight into the etiology of congenital obstructive uropathy and will help improve diagnosis, prognostication, family planning, and, ultimately, therapy for this condition.