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), 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.

Keywords: chronic kidney disease; end-stage renal disease; genetic renal disease; human genetics; transplantation.

Graphical abstract

Figure 1.

A monogenic cause of ESRD is identified in 32.7% of renal transplant recipients with onset of CKD before 25 years of age. Probands are categorized by clinical diagnostic group. Inner segments represent the numbers and fractions (in %) of transplant recipients that fall into one of six clinical diagnostic groups, as follows: CAKUT, 55 out of 104 (52%); SRNS, 21 out of 104 (20%); chronic GN, seven out of 104 (7%); renal cystic ciliopathies, nine out of 104 (9%); nephrolithiasis or nephrocalcinosis (NL/NC), three out of 104 (3%); and ESRD of unknown etiology, nine out of 104 (9%). Outer segments represent for each diagnostic group the relative fraction of patients in whom a molecular genetic diagnosis was established (darker colors). A disease-causing mutation was identified in 34 out of 104 families (32.7%). The distribution by clinical diagnostic group is as follows: a molecular diagnosis was established in ten out of 55 (18%) patients with CAKUT, nine out of 21 (43%) patients with SRNS, one out of seven (14%) patients with GN, seven out of nine (78%) patients with a renal cystic ciliopathy, three out of three (100%) patients with nephrolithiasis, and four out of nine (44%) patients with ESRD of unknown etiology.

Figure 2.

Relationship between the time point at which WES was performed and relevant diagnostic and treatment events in 104 renal transplant recipients. Each patient is denoted as a separate entry on the y-axis. Age is represented on the x-axis. For each patient, age at clinical presentation (triangles), dialysis initiation (open squares), renal transplantation (X), and genetic testing (orange vertical hatch) are depicted. Patients in whom a molecular genetic diagnosis was made are on the top, and depicted as solid lines on a white background. Patients in whom no genetic mutations were identified are shown as dashed lines on a gray background. Some patients received a renal transplant preemptively and never required dialysis. For most patients, genetic testing on a research basis was completed after kidney transplantation because of the retrospective nature of this study. Patient data are grouped by clinical diagnosis within the same categories depicted in Figure 1, i.e., (A) CAKUT, (B) SRNS, (C) chronic GN, (D) renal cystic ciliopathies, (E) nephrolithiasis/nephrocalcinosis, and (F) ESRD of unknown etiology.