Polycystic kidney disease 2

Polycystic kidney disease 2 is a renal genetic disease caused by variants in PKD2 (structured inheritance unpopulated, graded open; the definition describes autosomal dominant disease), acting through haploinsufficiency. Within this volume's rankable burden cohort it sits at residual rank 11 of 23, where established therapy is partially disease-modifying. That order is a provisional [H]-grade prioritisation device, not a registry-locked ranking.

Polycystic kidney disease 2 is inherited as mode of inheritance not populated in the structured source and acts by haploinsufficiency ([L]). Its pre-treatment burden proxy is 0.5167 and, after the established therapy's efficacy offset e = 0.3000 is applied, its residual burden score is 0.3617 ([H]), placing it at residual rank 11 of 23.

Gene, inheritance, and molecular mechanism

Polycystic kidney disease 2 is inherited as not_stated [O] and is classified mechanistically as haploinsufficiency [L]. PKD2 encodes polycystin-2, a calcium-permeable channel of the renal primary cilium. Reduced function raises cyst-driving intracellular cAMP, so fluid-filled cysts expand in both kidneys over decades.

Inheritance source: (structured MedGen field). Mechanism source: clingen:HI_score_3:2026-06-17; genes=PKD2; PMID:8650545,9402976. These are observed, cited inputs; the inheritance and mechanism classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

The cited definition characterises this as autosomal dominant polycystic kidney disease: bilateral kidney cysts with progressive loss of renal function, liver cysts, and an increased risk of intracranial aneurysm. (The structured MedGen mode-of-inheritance field is unpopulated for this concept.)

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 173910,613095); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Reproducible burden position

Of the five axes, 3 are scored (the rankability cut is ≥ 3 of 5); the pre-treatment composite is the renormalised mean over the scored axes, raw_burden = 0.5167. The registry-grade [L] axes here are onset and progression (onset from the Orphanet AverageAgeOfOnset register / HPO). Severity remains an [H] inference from the cited clinical definition.

Because those axes carry [H] inferences, this position is a provisional [H] prioritisation device, not a registry-locked ranking.

The natural-history registry passes have been run against Orphanet/Orphadata (CC BY 4.0, R6) and the openly published GBD 2013 disability-weights table (Salomon et al., CC BY, R7). R6 lifts onset to registry-grade [L] across most of the cohort (earliest AverageAgeOfOnset category, entity-anchored per ORPHAcode, Exact OMIM↔ORPHA only); R7 lifts disability to [L] where one dominant untreated sequela maps to a named GBD health state (published disability weight binned by declared cut-points), and independently corroborates a mortality axis from PMC survival literature where a quantitative disease-typical figure exists. Severity now lifts to registry [L] for the one disease whose dominant sequela carries a cited HPO Severity-modifier annotation (the HP:0012824 subtree, R8); for the rest the open HPO severity annotations are feature-level (using one feature as the disease tier would be a category error), so severity stays [H]/[O] with the obstacle named. Progression lifts to registry [L] where a cited PMC open-access source states a disease-level magnitude for the dominant untreated sequela and the frozen R3 tier function derives the tier from that verbatim sentence (R9, curated dominant-sequela join, non-spectrum); for the rest progression stays [H]/[O]. The OMIM clinical synopsis (the disease-level alternative) is API-key-gated and the key is unobtainable for an individual researcher — that path is removed, not guessed.

Established treatment and residual burden

The established disease-directed approach is vasopressin V2-receptor antagonist (tolvaptan) in rapid progressors, with supportive renal care and renal replacement. Mechanistically: tolvaptan lowers cyst-driving intracellular cAMP, slowing cyst growth [L].

Its effect on natural history is classified disease-modifying (partial), mapping to an efficacy offset e = 0.3000 and a residual factor R_treat = 0.7000. Applied to the pre-treatment proxy this gives the residual burden score 0.3617, moving the disease from raw rank 23 to residual rank 11 (shift 12).

Evidence tier: accession-dated to the GeneReviews NBK1246 Management section [L] (initial posting January 10, 2002; last revision September 29, 2022; retrieved 2026-06-18; corroborating term(s): “vasopressin, antagonist, tolvaptan, rapid”). The natural-history axis grades remain a mix of [L] (GeneReviews-corroborated) and [H] (definition-only), so the burden order is still provisional.