Kidney Week

Abstract: FR-OR035

Clinical Utility of Whole-Exome Sequencing for CKD

Session Information

• Genetically-Defined Kidney Diseases: From Variant Calling to Treatment
  November 03, 2017 | Location: Room 392, Morial Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Genetic Diseases of the Kidney

• 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

• Groopman, Emily, Columbia University, New York, New York, United States

Emily Groopman



Emily Groopman is an MD/PhD student in the Division of Nephrology at Columbia University. Her research investigates the utility of genomic sequencing technologies for molecular diagnosis and gene discovery in nephrology. She aspires to a career as an academic nephrologist, applying genomics to deliver personalized care to patients with kidney disease.

• Marasa, Maddalena, Columbia University, New York, New York, United States

Maddalena Marasa,

• Milo Rasouly, Hila, Columbia University, New York, New York, United States

Hila Milo Rasouly,

• Mitrotti, Adele, Columbia University, New York, New York, United States

Adele Mitrotti,

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk,

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi,

• Goldstein, David B., Columbia University, New York, New York, United States

David B. Goldstein,

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi,

Background

Whole-exome sequencing (WES) has recently been introduced into clinical diagnostics, but its value for adult constitutional disorders requires further evaluation. We are assessing the diagnostic yield of WES in a large cohort of adults with all-cause CKD or ESRD recruited at Columbia University (N=1920).

Methods

WES was performed in 1920 patients evaluated at Columbia University for various forms of CKD. To date, the exomes of 765 patients have been analyzed using American College of Medical Genetics (ACMG) guidelines for clinical sequence interpretation.

Results

97.4% of 765 patients were adults and 51.0% were non-Caucasian; 54% had glomerulopathy, 7% had congenital defects, and 17.5% had CKD of unknown etiology. In total, 82 (10.7%) patients had a diagnostic variant for a genetic form of nephropathy. Among these diagnosed cases, 19.5% had presented with “CKD of unknown origin” and 41.5% noted no family history of nephropathy. In 47.6% of diagnosed cases, the molecular diagnosis confirmed the clinical diagnosis (e.g., Alport syndrome); in 52.4% it clarified the diagnosis (e.g., UMOD mutation in a patient with tubulointerstitial nephropathy) or provided an alternative diagnosis (e.g., Dent disease in a case of suspected glomerulopathy). Diagnostic variants were mainly found in genes for glomerulopathies (65.9%), followed by those for cystic disease (11.0%), tubulointerstitial disease (9.8%), other nephropathies (9.8%), and congenital anomalies (3.7%). In addition, 6 patients (0.8%) had a secondary, pathogenic variant in one of the 59 ACMG actionable genes. In the majority of cases, the results impacted clinical decision-making, through aspects such as initiation of targeted surveillance, family counseling, selection of transplant donors, and changes in therapy.

Conclusion

In a large all-cause CKD cohort, WES gave a molecular diagnosis for 1 in 10 patients, and in 52.4% of positive cases, pinpointed an etiology not detected using traditional diagnostics, impacting clinical care. The completion of this study will inform the utility of genetic testing for nephropathy across broad demographic subgroups and etiologic subtypes.

Funding

• NIDDK Support