Exome sequencing, a technique for sequencing the protein-coding genes in a genome, can identify patients with kidney diseases due to genetic variants, a finding that could have implications for clinical management, according to investigators.

In a study involving exome sequencing and diagnostic analysis in 2 cohorts totaling 3315 patients with chronic kidney disease (CKD), principal investigator Ali G. Gharavi, MD, of Columbia University College of Physicians and Surgeons in New York, and colleagues detected diagnostic variants in 307 patients (9.3%). Of these, 206 (67%) had an autosomal dominant disease, 42 (14%) had an autosomal recessive disease, and 54 (18%) had an X-linked disease, the investigators reported in the New England Journal of Medicine.

Diagnostic yield was highest among patients with a clinical diagnosis of congenital or cystic renal disease (23.9%) and patients with nephropathy of unknown origin (17.1%), according to Dr Gharavi’s team.

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The 3315 patients included 1128 from AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) and 2187 patients from the Columbia University Medical Center (CUMC) Genetic Studies of Chronic Kidney Disease.

Clinical diagnoses were classified according to broad etiologic category, Dr Gharavi and colleagues stated. For patients in the AURORA cohort, only these broad categories and diagnostic codes for their major clinical features were available. For patients in the CUMC cohort, patients’ electronic health records provided more detailed clinical information. For the 167 patients in the CUMC cohort who had a genetic diagnosis, Dr Gharavi’s group used the more detailed clinical data to assess the diagnostic utility of the genetic findings from exome sequencing and their potential implications for clinical management.

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Genetic diagnoses “gave new clinical insight” for 122 (73%) of the patients, according to the investigators. “For 65 patients, it enabled identification of a specific underlying cause within the broader category of clinically suspected disease—for example, by pinpointed the precise genetic subtype of focal segmental glomerulosclerosis or cystic disease.”

Genetic findings reclassified disease in 18 patients. For 39 patients who had been referred with nephropathy of unknown origin, exome sequencing identified a molecular cause of the nephropathy. Genetic diagnoses could inform therapeutic decisions for 84 patients (50%), for example, by avoiding immunosuppression among patients with monogenic forms of focal segmental glomerulosclerosis, according to the investigators.

“Overall, these findings emphasize the high degree of genetic and phenotypic heterogeneity of hereditary nephropathies and show the extent to which genetic testing can help to resolve clinical diagnostic challenges,” the authors wrote.


Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2018. DOI: 10.1056/NEJMoa180689