Abstract: SA-PO418
Targeted Next-Generation Sequencing of Nephropathy Genes in Non-Diabetic and Diabetic Kidney Disease Patients Facilitates Clinical Diagnoses
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Fierro Morales, Julio Cesar, University of Utah, Salt Lake City, Utah, United States
- Wright, Andrew Hunter, University of Utah, Salt Lake City, Utah, United States
- Frodsham, Scott G., University of Utah, Salt Lake City, Utah, United States
- Pezzolesi, Melissa H., University of Utah, Salt Lake City, Utah, United States
- Lazaro guevara, Jose M., University of Utah, Salt Lake City, Utah, United States
- Pezzolesi, Marcus G., University of Utah, Salt Lake City, Utah, United States
Background
For patients with concomitant diabetes and chronic kidney disease (CKD), diabetes is often assumed to be the underlying cause of their kidney disease. Without histopathological evidence, however, it’s unclear if such patients have diabetic kidney disease (DKD), nondiabetic kidney disease (NDKD), or concurrent DKD and NDKD. To examine the utility of targeted next-generation sequencing (NGS) in facilitating clinical diagnoses in CKD, we coupled this technology with a custom nephropathy gene panel to determine the genetic cause of CKD in NDKD and DKD patients from the Utah Kidney Study.
Methods
Targeted NGS of 345 nephropathy genes was performed in 186 patients (87 NDKD and 99 DKD). Identified variants were prioritized by predicted effect on protein function, frequency (minor allele frequency (MAF) < 0.1%), and a CADD-based mutation significance cutoff (MSC) at the 95% confidence interval for ClinVar.
Results
After applying a MAF filter and MSC impact score cutoff, retaining only variants marked as highly likely to be deleterious, we identified 563 rare, functional variants, 113 of which are novel. These included 509 nonsynonymous, 20 nonsense, 24 frameshift, and 10 splicing variants. No enrichment of these variants was observed in NDKD patients when compared to DKD patients (P=0.55); there was, however, a modest, non-significant excess of novel rare variants in the NDKD cohort (P=0.15). An excess of rare variants was identified in the NDKD cohort in several genes, including COL4A5 and PKD2. Conversely, variants in DYNC2H1, ATP7B, NEK8, and ACE were enriched in the DKD cohort. Interestingly, variants PKHD1 and CUBN were nearly equally distributed between the two cohorts.
Conclusion
We identified many rare and novel variants in known nephropathy genes in both NDKD and DKD patients. Our findings suggest that many DKD patients likely have concomitant diabetes and non-diabetic CKD that can be attributed to a genetic cause. Our study suggests that targeted NGS may prove useful as a diagnostic tool to enable an accurate molecular CKD diagnosis, particularly in patients whose underlying CKD cause is incorrectly attributed to their diabetes.
Funding
- Private Foundation Support