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.
Neurology. 2018 Dec 4;91(23):e2170-e2181. doi: 10.1212/WNL.0000000000006614. Epub 2018 Nov 9.
To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.
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 exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.
We identified 2 different variants in exon 38 from the 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 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.
The 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 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 knockout mouse model ( ) 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 a highly plausible candidate gene in cerebrovascular disease.
通过全外显子测序，鉴定与颅内动脉瘤（IA）或蛛网膜下腔出血（SAH）发病相关的新基因。
我们对 3 个具有常染色体显性 IA/SAH 遗传模式的家族中的 13 个人进行了全外显子测序，以寻找疾病的候选基因。此外，我们对 161 名特发性 IA/SAH 患者的外显子 38 进行了测序，以寻找潜在致病变异的其他携带者。
我们在外显子 38 中发现了 2 个不同的变异，这两个变异分别位于 2 个具有 IA 或 SAH 的不同家族的受影响成员之间（p.R2728C 和 p.V2811L）。对 164 个具有 SAH 或 IA 的样本进行了外显子 38 的 Sanger 测序。发现了另外 5 个错义突变。我们还在一个有神经血管疾病史的家族中发现了第二个 p.V2811L 携带者。
该基因编码的蛋白参与有丝分裂间期和有丝分裂中微管的核形成和组织过程。该基因的双等位基因功能丧失突变导致一种原始侏儒症（小头骨发育不良原始侏儒症 II 型），约 50%的这些患者会出现神经血管异常，包括 IA 和 SAH。此外，之前发表的一个完全的 基因敲除小鼠模型（）显示了广泛的血管异常，包括颅内出血。我们家族中的变异位于高度保守的 PCNT 蛋白-蛋白相互作用结构域，因此 是脑血管疾病的一个高度合理的候选基因。
