Genomic Testing in Patients with Kidney Failure of an Unknown Cause: A National Australian Study

Abstract

Key Points:

1. Twenty-five percent of those with unexplained kidney failure have a monogenic cause.

2. Whole genome sequencing with broad gene panel analysis is a feasible diagnostic approach in nephrology.

Background: The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis, and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause.

Methods: We prospectively recruited 100 participants who reached CKD stage 5 at the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. The primary analysis was targeted to 388 kidney-related genes with second-tier, genome-wide, and mitochondrial analysis.

Results: The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4), and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked, or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of the 25 participants.

Conclusions: In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

Graphical abstract

Figure 1

Study flow chart. Flow chart of study methodology and recruitment process. CAKUT, congenital anomalies of the kidney and urinary tract.

Figure 2

Cohort characteristics. (A) Age of kidney failure in all participants, with positive and negative results highlighted. (B) Overview of diagnostic yield within the cohort. The figure legend is applicable to both (A) and (B). Circles=female probands; squares=male probands; solid blue represents a disease-causing or positive result; gray represents a VUS; white represents a negative result; positive=pathogenic or LP result. LP, likely pathogenic; VUS, variant of uncertain significance.

Figure 3

Diagnoses identified in the HIDDEN study. (A) Summary of overall study findings: the inner circle represents disease-groups identified, middle circle represents genes with disease-causing variant identified through the study, and outer circle represents the inheritance pattern of identified diagnoses. (B) Family history of kidney disease and positive and negative results. ADTKD, autosomal dominant tubulointerstitial kidney disease. HIDDEN, wHole genome Investigation to iDentify unDEtected Nephropathies.

Figure 4

Expanding the phenotypic spectrum of known genetic kidney diseases. (A) Pedigree for participant A0052. (B) Abdominal ultrasound images of left and right kidneys in longitudinal view, demonstrating bilateral renal cysts. (C) Pedigree for participant A0012. (D) Periodic acid–Schiff stain 200× magnification demonstrating complete loss of tubular basement membrane (blue arrow head) and membrane reduplication (black arrow) seen within the same tubule. (E) Hematoxylin and eosin–stained slide 200× magnification with red arrow showing interstitial fibrosis and blue arrowheads showing interstitial inflammatory cell infiltrate. (F) Electron microscopy of tubule 3000× magnification with red arrow showing atrophic tubular basement membrane and blue arrowhead showing reduplicated, thickened tubular basement membrane. The black arrowhead shows split in the tubular basement membrane.