Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients
Authors: Nina Mann, Daniela A. Braun, Kassaundra Amann, Weizhen Tan, Shirlee Shril, Dervla M. Connaughton, Makiko Nakayama, Ronen Schneider, Thomas M. Kitzler, Amelie T. van der Ven, Jing Chen, Hadas Ityel, Asaf Vivante, Amar J. Majmundar, Ankana Daga, Jillian K. Warejko, Svjetlana Lovric, Shazia Ashraf, Tilman Jobst-Schwan, Eugen Widmeier, Hannah Hugo, Shrikant M. Mane, Leslie Spaneas, Michael J.G. Somers, Michael A. Ferguson, Avram Z. Traum, Deborah R. Stein, Michelle A. Baum, Ghaleb H. Daouk, Richard P. Lifton, Shannon Manzi, Khashayar Vakili, Heung Bae Kim, Nancy M. Rodig, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Case reports describe scenarios in which previously undiagnosed genetic disorders, such as primary hyperoxaluria type 1, caused early allograft failure in kidney transplant recipients. Whole-exome sequencing (WES) has found that approximately 20% of pediatric patients with CKD have a relevant mutation, but the diagnostic yield of WES in kidney transplant recipients is not known. In this study of 104 kidney transplant recipients at a single center, use of WES provided a molecular genetic diagnosis for 34 out of 104 (32.7%) patients. Such diagnoses enabled identification of potential prospective consequences for many patients; in others, receiving the diagnosis earlier in the course of their disease might have mitigated negative consequences. The authors propose considering WES for any child or young adult with CKD. Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children’s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.