@article{b30fe741b1e949d79e3d6e80f9148bb8,
title = "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.",
author = "Sneh Lata and Maddalena Marasa and Yifu Li and Fasel, {David A.} and Emily Groopman and Vaidehi Jobanputra and Hila Rasouly and Adele Mitrotti and Rik Westland and Miguel Verbitsky and Jorda Nestor and Slater, {Lindsey M.} and Vivette D'Agati and Marcin Zaniew and Anna Materna-Kiryluk and Francesca Lugani and Gianluca Caridi and Luca Rampoldi and Aditya Mattoo and Newton, {Chad A.} and Rao, {Maya K.} and Jai Radhakrishnan and Wooin Ahn and Canetta, {Pietro A.} and Bomback, {Andrew S.} and Appel, {Gerald B.} and Corinne Antignac and Markowitz, {Glen S.} and Garcia, {Christine K.} and Krzysztof Kiryluk and Simone Sanna-Cherchi and Gharavi, {Ali G.}",
note = "Funding Information: 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. Funding Information: 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=M17-1309. Funding Information: The study was funded by the New York State Empire Clinical Research Investigator Program, the Renal Research Institute, and the National Human Genome Research Institute of the National Institutes of Health. The funding sources had no role in the design, conduct, and analysis of the study or in the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2018 American College of Physicians.",
year = "2018",
month = jan,
day = "16",
doi = "10.7326/M17-1319",
language = "English (US)",
volume = "168",
pages = "100--109",
journal = "Annals of internal medicine",
issn = "0003-4819",
publisher = "American College of Physicians",
number = "2",
}