Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

<bold>Background: </bold>The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.<bold>Objective: </bold>To study the diagnostic utility of WES in a selected referral population of adults with CKD.<bold>Design: </bold>Observational cohort.<bold>Setting: </bold>A major academic medical center.<bold>Patients: </bold>92 adults with CKD of unknown cause or familial nephropathy or hypertension.<bold>Measurements: </bold>The diagnostic yield of WES and its potential effect on clinical management.<bold>Results: </bold>Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.<bold>Limitation: </bold>The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.<bold>Conclusion: </bold>Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.<bold>Primary Funding Source: </bold>New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health. [ABSTRACT FROM AUTHOR]