A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1)

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonsingle gene disorder resulting in renal failure. It is generally an adultonset disease, but rarely, cases of severe childhood polycystic diseasearise in ADPKD families. The clear clinical anticipation in these pedigreeshas led to the suggestion that the mutation may be an unstabletrinucleotide repeat. We have now identified a nonsense mutation,Tyr3818Stop, in one such family (P117) within the major ADPKD gene,polycystic kidney disease 1 (PKD1). The mutation is shown to be a de novochange in the father, and of grandpaternal origin. PKD1 manifests astypical adult onset disease in the father, but is seen as severe disease,detected as enlarged polycystic kidneys in utero, in one of a pair ofdizygotic twins; the other twin has the mutation but no evidence of cysts,consistent with an adult onset disease course. The finding of the samestable mutation associated with very different disease severity in thisfamily indicates that phenotypic variation in PKD1 is not due to a dynamicmutation. It seems most likely that a small number of modifying factors mayradically affect the course of disease in PKD1; identification of suchfactors will have important prognostic implications in this disorder.