Diagnostic Utility of Exome Sequencing for Kidney Disease

Abstract

Background: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.

Methods: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.

Results: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.

Conclusions: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).

Figure 1.. Common Genetic Findings and the Clinical Diagnostic Spectrum.

Panel A shows the most common diagnostic genetic findings. In total, 312 genetic diagnoses, representing 66 distinct monogenic disorders, were detected in 307 patients, with 5 patients (2%) harboring dual molecular diagnoses (Tables S8 through S10 in Supplementary Appendix 1 and Table S7 in Supplementary Appendix 2). Of the 66 distinct monogenic disorders observed, 6 collectively accounted for 63% of the genetic diagnoses: autosomal dominant polycystic disease due to mutations in PKD1 (75 patients) or PKD2 (22); glomerulopathy due to mutations in COL4A3 (27), COL4A4 (21), or COL4A5 (44); and UMOD-associated tubulointerstitial disease (9). Percentages do not total 100 because of rounding. Panel B shows the clinical diagnostic spectrum of patients with diagnostic variants in these genes; the percentage of patients belonging to a given diagnostic category among all the patients found to have diagnostic variants in the gene is shown. Patients who had diagnostic findings for nephropathy associated with COL4A3, COL4A4, or COL4A5 or for UMOD-associated tubulointerstitial disease had a broad spectrum of clinical diagnoses. The clinical diagnostic spectrum that was observed for the other 60 genes, which accounted for the remaining 37% of genetic diagnoses, is shown alongside for comparison. The categories of clinical diagnoses are congenital or cystic renal disease, glomerulopathy, diabetic nephropathy, hypertensive nephropathy, tubulointerstitial disease, and nephropathy of unknown origin.