Inherited and acquired determinants of cystogenesis. The formation of cysts in ADPKD is viewed as being dependent on the balance between ADPKD gene dosage (and hence protein expression, particularly of PC1 at the plasma membrane) and the susceptibility of the renal tubule epithelium to its effects, the “cystogenic threshold.” The gene dosage is dependent on the nature of germline mutations in PKD1 and PKD2, other variants at the disease locus, modifier genes including PKHD1, HNF1B, and other ciliopathy genes, and somatic mutations (the classic “second hit”), and other factors affecting the expression levels of these genes. The cystogenic threshold seems to be strongly dependent on cell autonomous contextual factors such as the developmental stage and superimposition of environmental agents such as renal injury and infection, and can also potentially be affected by modifier genes. Cell nonautonomous local effects may alter the cystogenic threshold and account for a “snowball effect” in cyst appearance. In the graph, as gene dosage (solid blue line) dips below the cystogenic threshold (dashed red line), cysts will form (green area). As such, the interplay between decreasing gene dosage and increasing cystogenic threshold determines the onset, progression, and severity of cystic disease.