Investigation of Genomic Disorders in Chronic Kidney Disease

Chronic kidney disease (CKD) is a major public health problem with adverse outcomes. Genetics factors contribute to the etiology of CKD. Copy number variants (CNV) contribute significantly to human genetic variation. Chromosomal microarrays (CMA) allow for the reliable detection of submicroscopic CNV. Genomic disorders (GD) have been defined as diseases resulting from specific rare, recurrent, pathogenic CNVs and affect multiple systems. We have demonstrated, in pediatric CKD patients, that 1) CNV analysis can be an important diagnostic tool for CKD, 2) GDs and their underlying CNVs were implicated in the pathogenesis of clinically diverse forms of CKD, 3) GDs can provide a unifying explanation for the association of renal and extra-renal manifestations, and 3) CNV analysis can help identify novel causal gene- disease associations. In this study, we propose to investigate the contribution of CNVs to the genetic risk of CKD in adults as well as expand our findings in pediatric patients, taking advantage of existing CMA, WES and clinical data from 12,182 participants from national cohorts for CKD and more than 80,000 population controls. We will identify and establish the population frequency of CNVs in CKD patients; annotate CNVs and, following criteria adapted from the American College of Medical Genetics, classify them according to their degree of pathogenicity; establish the burden of known and novel GDs in CKD cases compared to controls, both in aggregate and for specific, recurrent GDs; and examine the role of known and novel GD for the risk, complications and comorbidities of CKD, determine associations of GD burden with clinical variables and assess the value of individual loci for predicting the severity and/or progression of kidney disease, and renal and extra-renal outcomes. We expect to show the usefulness of this approach to help diagnose and inform treatment and management of CKD and its comorbidities in both adult and pediatric patients; this study will substantially advance our understanding of the human genetic etiology and pathogenesis of CKD, and may potentially prove more broadly relevant to human disease associated with pathogenic copy number variants.