The most important extra-renal manifestation of
autosomal dominant polycystic kidney disease (
ADPKD) in terms of debilitating injury and premature death is the development of
intracranial aneurysms (IAs) and other vascular complications, resulting in
subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in
ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the
ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these
proteins leads to IA development in mouse models, suggests a direct role of these
proteins in the
vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5' half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without
ADPKD have identified a number of genes/
proteins that may be risk factors for the development of IAs. These candidate
proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in
ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions.