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

Abstract

Background: 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.

Objective: To study the diagnostic utility of WES in a selected referral population of adults with CKD.

Design: Observational cohort.

Setting: A major academic medical center.

Patients: 92 adults with CKD of unknown cause or familial nephropathy or hypertension.

Measurements: The diagnostic yield of WES and its potential effect on clinical management.

Results: 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.

Limitation: The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.

Conclusion: 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.

Primary funding source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

Figure. Kidney biopsy findings in a PARN mutation carrier (K018)

A. Low-power view of the renal cortex shows mild acute tubular injury and mild tubulointerstitial scarring. Glomeruli appear unremarkable (hematoxylin–eosin stain; original magnification, ×200). B. Low-magnification view of the renal medulla reveals more pronounced abnormalities. The tubular architecture is broadly disorganized, with a haphazard arrangement of tubules. The interstitium is notable for a diffuse increase in cellularity (hematoxylin–eosin stain; original magnification, ×100). C. The majority of tubules are lined by cuboidal to columnar epithelium. Flattened epithelium consistent with the thin limbs of the loop of Henle are difficult to discern (hematoxylin–eosin stain; original magnification, ×200). D. The interstitium is diffusely hypercellular, and the majority of the cellularity is composed of mesenchymal cells. Intermixed lymphocytes and plasma cells are also noted (hematoxylin–eosin stain; original magnification, ×200). E. High-magnification image shows columnar epithelium and apparent mesenchymal cuffing (hematoxylin–eosin stain; original magnification, ×600). F. A cyst within the medulla is lined by cuboidal to columnar epithelium (hematoxylin–eosin stain; original magnification, ×200).