PCNT point mutations and familial intracranial Aneurysms

Objective To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. Methods We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. Results We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. Conclusion 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 (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt-/-) 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

Data from: 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

PCNT and familial intracranial aneurysms-Supplemental data

(1) Detailed clinical description of additional PCNT mutation carriers (Text). (2) Supplementary Table 1. Fifty five variants were shared between the two patients from family 7042 and absent in the healthy individuals from this family. (3) Supplementary Table 2. Family 7019. Variants present in patients III.2 and III.4 not carried by healthy individuals IV.1 and IV.2 from family 7019. (4) Supplementary Table 3. PCNT exon 38 primers. (5) Supplementary Table 4. Microsatellites primers used for the haplotype sharing analysis in families 7019 and 8159; * = sizes based on the microsatellite analysis of 80 Caucasian samples. (6) Supplementary Table 5. Demographic data of the samples used to estimate the allele frequency of customized PCNT microsatellite. (7) Supplementary Table 6. Mean read depth (coverage) for the entire PCNT gene and for exon 38 for each individual with Whole Exome Sequencing data. (8) Supplementary Table 7. Sixty three variants were shared between the two patients from family 7042 and present also in the healthy individuals from this family. (9) Supplementary Table 8. Sixty three variants were shared between the two patients from family 7019 and present also in the healthy individuals from this family. (10) Supplementary Table 9. Family 7099 PCNT variants with MAF <1%. (11) Supplementary Figure 1. Patient 7019 III.2 CTA. (12) Supplementary Figure 2. Patient 7042 II.1 radiologic studies. (13) Supplementary Figure 3. Patient 7099 II.2 radiologic studies. (14) Supplementary Figure 4. Patient 8080 II.2 radiologic studies. (15) Supplementary Figure 5. Patient 8091 III.1 radiologic studies. (16) Supplementary Figure 6. Patient 8159 III.3 CTA. (17) Supplementary Figure 7. Haplotype reconstruction for families 7019 and 8159 sharing mutation p.Val2821Leu. (18) Supplementary Figure 8. Coding isoforms and processed transcripts of PCNT gene. (19) Supplementary Figure 9. Phylogenetic tree depicting evolutionary relationship of PCNT gene across species. (20) Supplementary Figure 10. A. PCNT gene conservation