PCNT point mutations and familial intracranial aneurysms

Objective: To identify novel genes involved in the etiology of intracranial aneurysms (IA) and / or subarachnoid hemorrhages (SAH) using whole exome sequencing. Methods. In the present study we performed whole exome sequencing in thirteen individuals from three families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. Additionally, we sequenced PCNT exon 38 in 161 sporadic IA/SAH patients in order to find additional carriers of potential pathogenic variants. Results. We identified two different variants in exon 38 from the PCNT gene shared between affected members from two different families with either IA or SAH (p.V2811L and p.R2728C). One hundred and sixty four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Seven missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. Conclusions. The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (MOPD-II) and ~50% of these patients will develop neurovascular abnormalities, including IAs and SAH. Additionally, a complete Pcnt knock-out mouse model (PcntM-/-) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.