Oswaldo Lorenzo-Betancor1, Patrick R Blackburn1, Emily Edwards1, Rocío Vázquez-do-Campo1, Eric W Klee1, Catherine Labbé1, Kyndall Hodges1, Patrick Glover1, Ashley N Sigafoos1, Alexandra I Soto1, Ronald L Walton1, Stephen Doxsey1, Michael B Bober1, Sarah Jennings1, Karl J Clark1, Yan Asmann1, David Miller1, William D Freeman1, James Meschia2, Owen A Ross2. 1. From the Department of Neuroscience (O.L.-B., C.L., K.H., P.G., A.I.S., R.L.W., O.A.R.), Center for Individualized Medicine (P.R.B., J.M.), Department of Health Sciences Research (P.R.B., Y.A.), Department of Neurology (E.E., R.V.-d-C., W.D.F., J.M.), Clinical Research Internship Study Program (P.G.), Department of Neurosurgery (D.M., W.D.F.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Center for Individualized Medicine (E.W.K.), Department of Health Sciences Research (E.W.K.), Department of Laboratory Medicine and Pathology (E.W.K.), Department of Clinical Genomics (E.W.K.), and Department of Biochemistry and Molecular Biology (A.N.S., K.J.C.), Mayo Clinic, Rochester, MN; Department of Biology (K.H., O.A.R.), Basic Research Internship in Neuroscience and Cancer, University of North Florida, Jacksonville; Program in Molecular Medicine (S.D.), University of Massachusetts Medical School, Worcester; Division of Genetics (M.B.B.), Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE; and Section of Clinical Genetics & Genetic Counseling (S.J.), St. Christopher's Hospital for Children, Philadelphia, PA. 2. From the Department of Neuroscience (O.L.-B., C.L., K.H., P.G., A.I.S., R.L.W., O.A.R.), Center for Individualized Medicine (P.R.B., J.M.), Department of Health Sciences Research (P.R.B., Y.A.), Department of Neurology (E.E., R.V.-d-C., W.D.F., J.M.), Clinical Research Internship Study Program (P.G.), Department of Neurosurgery (D.M., W.D.F.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Center for Individualized Medicine (E.W.K.), Department of Health Sciences Research (E.W.K.), Department of Laboratory Medicine and Pathology (E.W.K.), Department of Clinical Genomics (E.W.K.), and Department of Biochemistry and Molecular Biology (A.N.S., K.J.C.), Mayo Clinic, Rochester, MN; Department of Biology (K.H., O.A.R.), Basic Research Internship in Neuroscience and Cancer, University of North Florida, Jacksonville; Program in Molecular Medicine (S.D.), University of Massachusetts Medical School, Worcester; Division of Genetics (M.B.B.), Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE; and Section of Clinical Genetics & Genetic Counseling (S.J.), St. Christopher's Hospital for Children, Philadelphia, PA. ross.owen@mayo.edu meschia.james@mayo.edu.
Abstract
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.
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.
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