Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Abstract

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), steroidresistant 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 WESrelated 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.

Risk of Cardiovascular Disease and Mortality in Young Adults With End-stage Renal Disease

“…Specifically, reported ESRD causative processes can be subject to misclassification, which has been noted in previous studies. [38][39][40] Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); ESRD, end-stage renal disease; NA, not applicable. a Adjusted for age and cause of ESRD with interaction, sex, and race.…”

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

“…Genetic renal disease makes up a significant proportion of chronic kidney disease (CKD) in children . At least 10% of adults and nearly all children who received renal replacement therapy have a genetic renal disease . CKD is caused to a large degree by congenital anomalies of the kidney and urinary tract (CAKUT), steroid‐resistant nephrotic syndrome (SRNS), chronic glomerulonephritis and renal cystic ciliopathies (nephronophthisis [NPHP]; and polycystic kidney disease [PKD]).…”

Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease

“…The utility of whole exome sequencing in differential diagnosis of CKD etiologies has recently been demonstrated in several large cohorts of both pediatric and adult patients with advanced CKD and ESRD. 8,9,35 Furthermore, deep intronic variants, mutations within variable number tandem repeats, such as the MUC1-dupC mutation, 36 and changes in regulatory regions, as shown by the recently identified promoter mutation in PMM2, 37 would have been missed by our approach. In addition, as NGS data were analyzed for copy number variations, this tool may not be as sensitive as the gold standard of multiplex ligationdependent probe amplification in regions of lower coverage.…”