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. Primary Funding Source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
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. Primary Funding Source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
Authors: Maja Tarailo-Graovac; Casper Shyr; Colin J Ross; Gabriella A Horvath; Ramona Salvarinova; Xin C Ye; Lin-Hua Zhang; Amit P Bhavsar; Jessica J Y Lee; Britt I Drögemöller; Mena Abdelsayed; Majid Alfadhel; Linlea Armstrong; Matthias R Baumgartner; Patricie Burda; Mary B Connolly; Jessie Cameron; Michelle Demos; Tammie Dewan; Janis Dionne; A Mark Evans; Jan M Friedman; Ian Garber; Suzanne Lewis; Jiqiang Ling; Rupasri Mandal; Andre Mattman; Margaret McKinnon; Aspasia Michoulas; Daniel Metzger; Oluseye A Ogunbayo; Bojana Rakic; Jacob Rozmus; Peter Ruben; Bryan Sayson; Saikat Santra; Kirk R Schultz; Kathryn Selby; Paul Shekel; Sandra Sirrs; Cristina Skrypnyk; Andrea Superti-Furga; Stuart E Turvey; Margot I Van Allen; David Wishart; Jiang Wu; John Wu; Dimitrios Zafeiriou; Leo Kluijtmans; Ron A Wevers; Patrice Eydoux; Anna M Lehman; Hilary Vallance; Sylvia Stockler-Ipsiroglu; Graham Sinclair; Wyeth W Wasserman; Clara D van Karnebeek Journal: N Engl J Med Date: 2016-05-25 Impact factor: 91.245
Authors: Jason L Vassy; Kurt D Christensen; Erica F Schonman; Carrie L Blout; Jill O Robinson; Joel B Krier; Pamela M Diamond; Matthew Lebo; Kalotina Machini; Danielle R Azzariti; Dmitry Dukhovny; David W Bates; Calum A MacRae; Michael F Murray; Heidi L Rehm; Amy L McGuire; Robert C Green Journal: Ann Intern Med Date: 2017-06-27 Impact factor: 25.391
Authors: Josef Coresh; Elizabeth Selvin; Lesley A Stevens; Jane Manzi; John W Kusek; Paul Eggers; Frederick Van Lente; Andrew S Levey Journal: JAMA Date: 2007-11-07 Impact factor: 56.272
Authors: David B Goldstein; Andrew Allen; Jonathan Keebler; Elliott H Margulies; Steven Petrou; Slavé Petrovski; Shamil Sunyaev Journal: Nat Rev Genet Date: 2013-06-11 Impact factor: 53.242
Authors: Yaping Yang; Donna M Muzny; Jeffrey G Reid; Matthew N Bainbridge; Alecia Willis; Patricia A Ward; Alicia Braxton; Joke Beuten; Fan Xia; Zhiyv Niu; Matthew Hardison; Richard Person; Mir Reza Bekheirnia; Magalie S Leduc; Amelia Kirby; Peter Pham; Jennifer Scull; Min Wang; Yan Ding; Sharon E Plon; James R Lupski; Arthur L Beaudet; Richard A Gibbs; Christine M Eng Journal: N Engl J Med Date: 2013-10-02 Impact factor: 91.245
Authors: Martin Kircher; Daniela M Witten; Preti Jain; Brian J O'Roak; Gregory M Cooper; Jay Shendure Journal: Nat Genet Date: 2014-02-02 Impact factor: 38.330
Authors: Peter D Stenson; Matthew Mort; Edward V Ball; Katy Evans; Matthew Hayden; Sally Heywood; Michelle Hussain; Andrew D Phillips; David N Cooper Journal: Hum Genet Date: 2017-03-27 Impact factor: 4.132
Authors: Colin C Pritchard; Joaquin Mateo; Michael F Walsh; Navonil De Sarkar; Wassim Abida; Himisha Beltran; Andrea Garofalo; Roman Gulati; Suzanne Carreira; Rosalind Eeles; Olivier Elemento; Mark A Rubin; Dan Robinson; Robert Lonigro; Maha Hussain; Arul Chinnaiyan; Jake Vinson; Julie Filipenko; Levi Garraway; Mary-Ellen Taplin; Saud AlDubayan; G Celine Han; Mallory Beightol; Colm Morrissey; Belinda Nghiem; Heather H Cheng; Bruce Montgomery; Tom Walsh; Silvia Casadei; Michael Berger; Liying Zhang; Ahmet Zehir; Joseph Vijai; Howard I Scher; Charles Sawyers; Nikolaus Schultz; Philip W Kantoff; David Solit; Mark Robson; Eliezer M Van Allen; Kenneth Offit; Johann de Bono; Peter S Nelson Journal: N Engl J Med Date: 2016-07-06 Impact factor: 91.245
Authors: Sophia Cameron-Christie; Charles J Wolock; Emily Groopman; Slavé Petrovski; Sitharthan Kamalakaran; Gundula Povysil; Dimitrios Vitsios; Mengqi Zhang; Jan Fleckner; Ruth E March; Sahar Gelfman; Maddalena Marasa; Yifu Li; Simone Sanna-Cherchi; Krzysztof Kiryluk; Andrew S Allen; Bengt C Fellström; Carolina Haefliger; Adam Platt; David B Goldstein; Ali G Gharavi Journal: J Am Soc Nephrol Date: 2019-05-13 Impact factor: 10.121
Authors: Dervla M Connaughton; Claire Kennedy; Shirlee Shril; Nina Mann; Susan L Murray; Patrick A Williams; Eoin Conlon; Makiko Nakayama; Amelie T van der Ven; Hadas Ityel; Franziska Kause; Caroline M Kolvenbach; Rufeng Dai; Asaf Vivante; Daniela A Braun; Ronen Schneider; Thomas M Kitzler; Brona Moloney; Conor P Moran; John S Smyth; Alan Kennedy; Katherine Benson; Caragh Stapleton; Mark Denton; Colm Magee; Conall M O'Seaghdha; William D Plant; Matthew D Griffin; Atif Awan; Clodagh Sweeney; Shrikant M Mane; Richard P Lifton; Brenda Griffin; Sean Leavey; Liam Casserly; Declan G de Freitas; John Holian; Anthony Dorman; Brendan Doyle; Peter J Lavin; Mark A Little; Peter J Conlon; Friedhelm Hildebrandt Journal: Kidney Int Date: 2019-02-14 Impact factor: 10.612