Renal hypodysplasia (RHD) is a congenital malformation of the kidney often associated with additional malformations and clinical complications. Overall, kidney and urinary tract malformations main complication is end-stage kidney failure (ESRD), and they account for up to 50% of pediatric and 7% of adult ESRD worldwide. The biological basis of RHD is poorly understood. Currently rare variants in known genes (single nucleotide variants and small insertion deletion variants, or SNVs) and rare copy-number variants (CNVs) only explain the cause of 10-20% of RHD, limiting the development of optimal diagnostic and prognostic tools. Interestingly, our preliminary data suggest that common variants are significantly associated with kidney and urinary tract malformations, pointing to another mechanism to resolve the missing heritability of RHD. The central hypothesis of this application is that comprehensive genetic approaches can advance our understanding of the biological basis of RHD. The rationale underlying the application is that all types of genetic variants (common and rare, SNVs and CNVs, de novo and inherited) can cause RHD, and that some of the comorbidities associated with RHD can help identify novel genes associated with syndromic RHD. To ensure a comprehensive analysis, we will pursue three aims: 1) As de novo variants are known to be an important mechanism for developmental disorders, we will analyze the burden of all types of de novo variants (SNVs, CNVs and non-coding variants). 2) As both inherited and de novo mutations contribute to RHD and have pleiotropic effects on the development of other organs, we will also utilize case-control approach. To increase our statistical power, we will then combine the results from the case-control analysis with the results from the de novo analysis, and take advantage of the large publicly available sequenced cohorts of patients with RHD comorbidities to perform a combined case-control analysis. 3) We will test whether common variants can increase the risk for RHD by performing genome-wide association analysis on a large set of cases and controls, and calculating a polygenic risk score to predict RHD (RHD- PRS). We will then analyze the association between the RHD-PRS to its comorbidities, and examine whether the RHD-PRS can modify the effect of rare pathogenic variants. Taken together, this application will investigate variation across a range of allele frequencies, to better understand their contribution to pleiotropy, penetrance and clinical severity of disease. The project benefits from the researchers expertise in Human Genetic, large cohorts of RHD cases, and recent support from the NIH X01 program for whole genome sequencing.