Hidden Monogenic Diagnoses in Young-Onset Dialysis After Exclusion of Clinically Apparent Polycystic Kidney Disease
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Background
Genomic reassessment may reveal clinically relevant diagnoses in patients with young-onset kidney failure despite established clinical diagnostic labels. We evaluated this approach after excluding clinically apparent polycystic kidney disease (PKD).
Methods
Among 1,139 patients receiving maintenance dialysis at participating Japanese facilities, 355 had initiated dialysis at age ≤50 years. After excluding 17 patients with clinically apparent PKD, 108 of 338 eligible patients underwent whole-genome sequencing through voluntary, nonrandom enrollment. Analysis included 465 nuclear candidate genes, mitochondrial DNA, and copy-number/structural variants. Clinically concordant diagnoses were adjudicated using integrated clinical and genetic evidence, with a separate pathogenic/likely pathogenic (P/LP)-supported subset.
Results
Diagnoses were identified in 10/108 participants (9.3%; 95% confidence interval, 5.1–16.2), comprising seven renal and three systemic/metabolic diagnoses. Nine diagnoses were P/LP-supported (8.3%; 95% confidence interval, 4.4–15.1). The remaining diagnosis was phenotype-based clinical Dent disease associated with a CLCN5 variant of uncertain significance. Diagnoses occurred across diabetic kidney disease, nephrosclerosis, chronic glomerulonephritis, unknown-cause, and other clinical categories. In a post hoc analysis excluding three participants with low target coverage, the integrated and P/LP-supported proportions were 9/105 (8.6%) and 8/105 (7.6%). Six exploratory findings were excluded from both diagnostic numerators. Gitelman syndrome was included as a clinically manifest renal disorder, although its contribution to kidney failure remained uncertain.
Conclusions
Integrated genomic assessment can uncover renal and systemic/metabolic diagnoses across conventional labels in young-onset kidney failure after exclusion of clinically apparent PKD. Nonrandom enrollment and variable sequencing coverage limit generalizability and interpretation of negative results.
