Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease

It is known that several of the most severe complications of autosomal-domi nant polycystic kidney disease, such as intracranial aneurysms, cluster in families. There have been no studies reported to date, however, that have a ttempted to correlate severely affected pedigrees with a particular genotyp e. Until recently, in fact, mutation detection for most of the PKD1 gene wa s virtually impossible because of the presence of several highly homologous loci also located on chromosome 16. In this report we describe a duster of 4 bp in exon 15 that are unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11-21 by use of long-range PCR, The two templates described were use d to analyze 35 pedigrees selected for study because they included individu als with either intracranial aneurysms and/or very-early-onset disease. We identified eight novel truncating mutations, two missense mutations not fou nd in a panel of controls, and several informative polymorphisms. Many of t he polymorphisms were also present in the homologous loci, supporting the i dea that they may serve as a reservoir for genetic variability in the PKD1 gene. Surprisingly, we found that three independently ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the possibility tha t particular genotypes may be associated with more-severe disease.