Hila Milo Rasouly, PhD *; Emily E. Groopman, BA *; Reuben Heyman-Kantor, BA; David A. Fasel, BS; Adele Mitrotti, MD; Rik Westland, MD, PhD; Louise Bier, MSc; Chunhua Weng, PhD; Zhong Ren, BS; Brett Copeland, BS; Priya Krithivasan, MSc; Wendy K. Chung, MD, PhD; Simone Sanna-Cherchi, MD; David B. Goldstein, PhD †; Ali G. Gharavi, MD †
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Acknowledgment: The authors thank the following individuals or groups for contributing control samples: K. Welsh-Bomer, C. Hulette, J. Burke, J. Hoover-Fong, A. Poduri, M. Connors, members of the Center for HIV/AIDS Vaccine Immunology, R. Buckley, R. Ottman, C. Depondt, S. Sisodiya, G. Cavalleri, N. Delanty, the Epi4K Consortium and Epilepsy Phenome/Genome Project, S. Hirose, the ALS Sequencing Consortium, the Washington University Neuromuscular Genetics Project, Carol Woods retirement community, Croasdaile Village retirement community, G. Nestadt, J. Samuels, E. Pras, D. Lancet, T. Young, C. Chen, M. Hauser, S. Delaney, A. Need, M. Walker, M. Sum, V. Shashi, the Undiagnosed Diseases Network, the Washington Heights–Inwood Columbia Aging Project, and the Utah Foundation for Biomedical Research.
Financial Support: By grant U01HG008680 to Drs. Gharavi and Weng from the National Human Genome Research Institute, grants R01DK080099 and U54DK104309 to Dr. Gharavi from the National Institute of Diabetes and Digestive and Kidney Diseases, grant R01MD009223 to Dr. Gharavi from the National Institute on Minority Health and Health Disparities, an American Society of Nephrology Donald E. Wesson Research Fellowship to Dr. Rasouly, and an F30 Fellowship (1F30DK116473-01) to Ms. Groopman from the National Institute of Diabetes and Digestive and Kidney Diseases, grants R01DK103184 and R01DK115574 to Dr Sanna-Cherchi from the National Institute of Diabetes and Digestive and Kidney Diseases. The collection of control samples and data was funded in part by the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (National Institute on Aging P30 AG028377), NIH RO1 HD048805, the National Institute of Allergy and Infectious Diseases (grant UO1AIO67854), the National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (U19-AI067854), the National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1-AI100645), the National Institute of Neurological Disorders and Stroke (award RC2NS070344), NIH U54 NS078059, NIH P01 HD080642, the J. Willard and Alice S. Marriott Foundation, the Muscular Dystrophy Association, the Nicholas Nunno Foundation, the JDM Fund for Mitochondrial Research, the Arturo Estopinan TK2 Research Fund, UCB, the Epi4K Gene Discovery in Epilepsy study (National Institute of Neurological Disorders and Stroke U01-NS077303) and Epilepsy Genome/Phenome Project (National Institute of Neurological Disorders and Stroke U01-NS053998), Biogen, the Ellison Medical Foundation New Scholar award (AG-NS-0441-08), the National Institute of Mental Health (award K01MH098126), B57 SAIC-Fredrick M11-074, 1R01MH097971 - 01A1, the American Academy of Child and Adolescent Psychiatry Pilot Research Award, the National Institute of Mental Health (grant RC2MH089915), an Endocrine Fellows Foundation Grant, the NIH Clinical and Translational Science Award Program (UL1TR000040), NIH U01HG007672, and the Washington Heights–Inwood Columbia Aging Project. Data collection and sharing for this project were supported by the Washington Heights–Inwood Columbia Aging Project (PO1AG07232, R01AG037212, and RF1AG054023) funded by the National Institute on Aging and National Center for Advancing Translational Sciences (grant UL1TR001873), the Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory, NewYork-Presbyterian Hospital, the Columbia University College of Physicians and Surgeons, and the Columbia University Medical Center. A philanthropic gift to Duke University from the David H. Murdock Foundation for Business and Culture, Duke University’s CTSA grant (NCATS UL1TR002553).
Disclosures: Dr. Gharavi reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute of the NIH 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=M18-1241.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive 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 Proctor & Gamble, Pfizer, and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See Appendix 2. Statistical code: Statistical methods are described in the Methods and supplementary files. Data set: All of the candidate pathogenic variants are listed in Supplement 4. Questions can be addressed to Dr. Gharavi (e-mail, firstname.lastname@example.org).
Corresponding Author: Ali G. 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; or David B. Goldstein, PhD, Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, Suite 1408, 701 West 168th Street, New York, NY 10032; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Chung: Department of Pediatrics, 1150 St. Nicholas Avenve Russ Berrie Pavilion, 6th Floor, Room 620, 10032 Columbia University Medical Center, New York, NY.
Drs. Rasouly, Mitrotti, Westland, Sanna-Cherchi, and Gharavi; Ms. Groopman; Mr. Heyman-Kantor; and Ms. Krithivasan: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032.
Ms. Bier, Mr. Ren, and Dr. Goldstein: Institute for Genomic Medicine, Columbia University Medical Center, 701 West 168th Street, New York, NY 10032.
Mr. Fasel and Dr. Weng: Department of Biomedical Informatics, Columbia University Medical Center, 622 West 168th Street, PH-20 Room 407, New York, NY 10032.
Mr. Copeland: Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Drive, Department 0419, La Jolla, CA 92093-0419.
Author Contributions: Conception and design: H.M. Rasouly, E.E. Groopman, D.B. Goldstein, A.G. Gharavi.
Analysis and interpretation of the data: H.M. Rasouly, E.E. Groopman, D.A. Fasel, R. Westland, Z. Ren, W.K. Chung, S. Sanna-Cherchi, D.B. Goldstein, A.G. Gharavi.
Drafting of the article: H.M. Rasouly, E.E. Groopman, C. Weng, A.G. Gharavi.
Critical revision of the article for important intellectual content: H.M. Rasouly, E.E. Groopman, R. Westland, L. Bier, W.K. Chung, S. Sanna-Cherchi, D.B. Goldstein, A.G. Gharavi.
Final approval of the article: H.M. Rasouly, E.E. Groopman, R. Heyman-Kantor, D.A. Fasel, A. Mitrotti, R. Westland, L. Bier, C. Weng, Z. Ren, B. Copeland, P. Krithivasan, W.K. Chung, S. Sanna-Cherchi, D.B. Goldstein, A.G. Gharavi.
Provision of study materials or patients: A. Mitrotti, C. Weng.
Statistical expertise: A. Mitrotti, Z. Ren, S. Sanna-Cherchi.
Obtaining of funding: C. Weng, A.G. Gharavi.
Administrative, technical, or logistic support: L. Bier, B. Copeland, P. Krithivasan, S. Sanna-Cherchi, A.G. Gharavi.
Collection and assembly of data: H.M. Rasouly, R. Heyman-Kantor, D.A. Fasel, R. Westland, L. Bier, C. Weng, S. Sanna-Cherchi.
Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists.
To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing.
Secondary analysis of genetic data.
A tertiary care academic medical center.
A convenience sample of exome sequence data from 7974 self-declared healthy adults.
Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders.
Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned.
Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses.
Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties.
National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.
Rasouly HM, Groopman EE, Heyman-Kantor R, et al. The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing. Ann Intern Med. 2019;170:11–21. [Epub ahead of print 27 November 2018]. doi: https://doi.org/10.7326/M18-1241
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Published: Ann Intern Med. 2019;170(1):11-21.
Published at www.annals.org on 27 November 2018
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