Sneh Lata, PhD; Maddalena Marasa, MD; Yifu Li, MD; David A. Fasel, BS; Emily Groopman, BA; Vaidehi Jobanputra, PhD; Hila Rasouly, PhD; Adele Mitrotti, MD; Rik Westland, MD, PhD; Miguel Verbitsky, PhD; Jordan Nestor, MD; Lindsey M. Slater, MD; Vivette D'Agati, MD; Marcin Zaniew, MD; Anna Materna-Kiryluk, MD; Francesca Lugani, MD; Gianluca Caridi, PhD; Luca Rampoldi, PhD; Aditya Mattoo, MD; Chad A. Newton, MD; Maya K. Rao, MD; Jai Radhakrishnan, MD; Wooin Ahn, MD; Pietro A. Canetta, MD; Andrew S. Bomback, MD; Gerald B. Appel, MD; Corinne Antignac, MD; Glen S. Markowitz, MD; Christine K. Garcia, MD; Krzysztof Kiryluk, MD; Simone Sanna-Cherchi, MD; Ali G. Gharavi, MD
Acknowledgment: The authors thank all study participants for contributing to this effort, David Goldstein and the Columbia Institute for Genomic Medicine for providing annotation tools and data from in-house controls, and Adam Platt for helpful comments.
Grant Support: By a New York State Empire Clinical Research Investigator Program grant, a research grant from the Renal Research Institute, and grant U01HG008680 from the National Human Genome Research Institute of the National Institutes of Health. Dr. Sanna-Cherchi is supported by grant 1R01DK103184 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
Disclosures: Dr. Newton reports grants from National Institutes of Health during the conduct of the study. Dr. Bomback reports grants from the National Institute on Minority Health and Health Disparities of the National Institutes of Health during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-1319.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol and data set: Available from Dr. Gharavi (e-mail, firstname.lastname@example.org). Statistical code: Not applicable.
Requests for Single Reprints: Ali Gharavi, MD, Department of Medicine, Division of Nephrology, Columbia University, 1150 Saint Nicholas Avenue, Russ Berrie Pavilion #413, New York, NY 10032; e-mail, email@example.com.
Current Author Addresses: Dr. Lata: Claritas Genomics, 99 Erie Street, Cambridge, MA 02139.
Drs. Marasa, Rao, Radhakrishnan, Ahn, Canetta, Bomback, and Appel: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, 622 West 168th Street, New York, NY 10032.
Drs. Li, Rasouly, Mitrotti, Westland, Verbitsky, Nestor, Kiryluk, Sanna-Cherchi, and Gharavi; Mr. Fasel; and Ms. Groopman: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, 1150 Saint Nicholas Avenue, New York, NY 10032.
Dr. Jobanputra: New York Genome Center, 101 Avenue of the Americas, New York, NY 10013.
Dr. Slater: Nephrology Associates, 4923 Ogletown Stanton Road #200, Newark, DE 19713.
Drs. D'Agati and Markowitz: Department of Pathology, College of Physicians and Surgeons, Columbia University, Room VC14-224, 630 West 168th Street, New York, NY 10032.
Dr. Zaniew: Osiedle Zwyciestwa 5H/27, 61-644 Poznań, Poland.
Dr. Materna-Kiryluk: Department of Medical Genetics, Poznan University of Medical Science, 8 Rokietnicka Street, 60-806 Poznań, Poland.
Drs. Lugani and Caridi: Istituto Giannina Gaslini, Largo G. Gaslini 5, 16148 Genova, Italy.
Dr. Rampoldi: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Dr. Mattoo: New York University Division of Nephrology, 560 1st Avenue #251, New York, NY 10016.
Drs. Newton and Hines: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390.
Dr. Antignac: Imagine Institute, 24 Boulevard de Montparnasse, 75015 Paris, France.
Author Contributions: Conception and design: S. Lata, M. Marasa.
Analysis and interpretation of the data: S. Lata, M. Marasa, Y. Li, D.A. Fasel, E. Groopman, V. Jobanputra, H. Rasouly, A. Mitrotti, V. D'Agati, G. Caridi, C.A. Newton, C. Antignac, C.K. Garcia, S. Sanna-Cherchi, A.G. Gharavi.
Drafting of the article: S. Lata, M. Marasa, F. Lugani, G.S. Markowitz, A.G. Gharavi.
Critical revision of the article for important intellectual content: E. Groopman, R. Westland, F. Lugani, L. Rampoldi, M.K. Rao, A.S. Bomback, G.B. Appel, C. Antignac, G.S. Markowitz, K. Kiryluk, S. Sanna-Cherchi, A.G. Gharavi.
Final approval of the article: S. Lata, M. Marasa, Y. Li, D.A. Fasel, E. Groopman, V. Jobanputra, H. Rasouly, A. Mitrotti, R. Westland, M. Verbitsky, J. Nestor, L.M. Slater, V. D'Agati, M. Zaniew, A. Materna-Kiryluk, F. Lugani, G. Caridi, L. Rampoldi, A. Mattoo, C.A. Newton, M.K. Rao, J. Radhakrishnan, W. Ahn, P.A. Canetta, A.S. Bomback, G.B. Appel, C. Antignac, G.S. Markowitz, C.K. Garcia, K. Kiryluk, S. Sanna-Cherchi, A.G. Gharavi.
Provision of study materials or patients: M. Marasa, L.M. Slater, V. D'Agati, A. Materna-Kiryluk, F. Lugani, G. Caridi, A. Mattoo, M.K. Rao, J. Radhakrishnan, P.A. Canetta, A.S. Bomback, G.S. Markowitz, S. Sanna-Cherchi.
Statistical expertise: K. Kiryluk, A.G. Gharavi.
Obtaining of funding: S. Lata, A.G. Gharavi.
Administrative, technical, or logistic support: S. Lata, Y. Li, M. Verbitsky, C.A. Newton, M.K. Rao.
Collection and assembly of data: S. Lata, M. Marasa, Y. Li, A. Mitrotti, R. Westland, M. Verbitsky, J. Nestor, M. Zaniew, A. Materna-Kiryluk, F. Lugani, C.A. Newton, W. Ahn, P.A. Canetta, G.S. Markowitz, S. Sanna-Cherchi.
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.
To study the diagnostic utility of WES in a selected referral population of adults with CKD.
A major academic medical center.
92 adults with CKD of unknown cause or familial nephropathy or hypertension.
The diagnostic yield of WES and its potential effect on clinical management.
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.
The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.
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.
New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
Lata S, Marasa M, Li Y, Fasel DA, Groopman E, Jobanputra V, et al. Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study. Ann Intern Med. ;168:100–109. doi: 10.7326/M17-1319
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Published: Ann Intern Med. 2018;168(2):100-109.
Published at www.annals.org on 5 December 2017
Chronic Kidney Disease, Nephrology.
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