From Guidelines to Practice: Pilot Implementation and Analytical Boundaries of a Focused ADPKD-Spectrum Gene Panel

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Background/Objectives: KDIGO supports molecular testing in selected autosomal dominant polycystic kidney disease (ADPKD) scenarios and targeted next-generation sequencing panels when broader evaluation is warranted; however, gene inclusion alone establishes neither analytical completeness nor clinical reportability. Methods: We designed and evaluated a 28-gene ADPKD-spectrum hybrid-capture panel in a 16-sample, two-configuration pilot using 694 analytical target intervals per sample. Multiplex ligation-dependent probe amplification assessed dosage in suspected PKD1-related disease or TSC2/PKD1 contiguous-gene deletion, and whole-exome sequencing selectively supported short-read reidentification. Results: In the primary eight-sample dataset, 4592/5552 observations (82.7%) had interval mean depth ≥20×, 4256/5552 (76.7%) had interval minimum depth ≥20×, and 89.6% of interval-record bases reached ≥10×. Nine genes (FLCN, GANAB, HNF1B, PRKCSH, REN, SEC61A1, TSC2, UMOD and VHL) met mean depth ≥20× throughout; six also met the minimum-depth criterion. For PKD1, 45/46 intervals met both criteria in all samples, but exon 1 remained undercovered, and nominal depth in duplicated sequence did not establish authentic-locus callability. Signals were observed at all four positive-comparator loci, although two lacked sufficient support for independent reporting. Seven of nine panel-first cases yielded observations: one HNF1B and one unique-locus PKD1 finding were supported, whereas four duplicated-sequence PKD1 findings remained confirmation-dependent. Conclusions: Responsible implementation requires explicit analytical boundaries and staged complementary testing.

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