BACKGROUND-Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS-We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS-In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS-Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.) Targeted capture and sequencing of the protein-coding regions of the genome through exome sequencing is increasingly applied as a first-line diagnostic tool in clinical medicine, particularly for the diagnosis of metabolic and neurodevelopmental disorders in children, 1,2 as well as for the detection of causal mutations in cancer. 3-5 In those contexts, exome sequencing can inform medical management, including the choice of therapy. 1,6-9 However, the usefulness of this approach has not been systematically studied for most constitutional disorders in adults. Because the diagnostic yield of exome sequencing can vary according to the clinical disorder and the population studied, 9 thorough investigations across different constitutional disorders are needed to inform its use in clinical practice. Chronic kidney disease affects more than 10% of people worldwide, with substantial associated morbidity and mortality and a high burden in health care spending. 10 Yet the