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N Engl J Med. 2019 Jan 10;380(2):142-151. doi: 10.1056/NEJMoa1806891. Epub 2018 Dec 26.

Diagnostic Utility of Exome Sequencing for Kidney Disease.

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From the Departments of Medicine (E.E.G., M.M., H.M.-R., Y.L., J.Z., J.N., P.K., W.Y.L., A.M., S. Piva, B.H.K., D.C., R.R., D.B., M.D., H.S., X.M., K.M., O.B., J.R., P.C., G.B.A., A.S.B., W.A., D.J.C., R.J.C., G.K.D., M.K.R., S.M., S.S.-C., K.K., A.G.G.) and Pediatrics (N.S.U.), Division of Nephrology, the Departments of Pathology (V.S.A.), Biomedical Informatics (D.A.F., C.W.), and Urology (S.A.), the Institute for Genomic Medicine (S.K., B.C., Z.R., J.B., C.D.M., C.M.M., N.D., D.B.G., A.G.G.) and the Department of Genetics and Development (D.B.G.), Hammer Health Sciences, and the Department of Epidemiology, Mailman School of Public Health (S.M.), Columbia University, New York; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, Innovative Medicines and Early Development (IMED) Biotech Unit, Cambridge, United Kingdom (S.C.-C., S. Petrovski, C.H., J.F., R.M., A.P.); and the Department of Medical Science, Renal Unit, Uppsala University Hospital, Uppsala, Sweden (B.C.F.).



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.


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.


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.


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.).

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