Whole-exome sequencing reveals known and novel variants in a cohort of intracranial vertebral–basilar artery dissection (IVAD)


Intracranial vertebral–basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, http://www.discostudy.org/, n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.

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  1. 1.

    Balik V, Yamada Y, Talari S,  Kei Y, Sano H, Suyama D, et al. State-of-art in surgical treatment of dissecting posterior circulation intracranial aneurysms. Neurosurg Rev. 2016;41:31–45.

  2. 2.

    Kaufmann TJ, Huston J 3rd, Mandrekar JN, Schleck CD, Thielen KR, Kallmes DF. Complications of diagnostic cerebral angiography: evaluation of 19,826 consecutive patients. Radiology. 2007;243:812–9.

  3. 3.

    Ramgren B, Cronqvist M, Romner B, Brandt L, Holtas S, Larsson EM. Vertebrobasilar dissection with subarachnoid hemorrhage: a retrospective study of 29 patients. Neuroradiology. 2005;47:97–104.

  4. 4.

    Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.

  5. 5.

    Giossi A, Ritelli M, Costa P, Morotti A, Poli L, Del Zotto E, et al. Connective tissue anomalies in patients with spontaneous cervical artery dissection. Neurology. 2014;83:2032–7.

  6. 6.

    Fujita D, Takeda N, Morita H, Kato M, Nishimura H, Inuzuka R, et al. A novel mutation of TGFBR2 causing Loeys-Dietz syndrome complicated with pregnancy-related fatal cervical arterial dissections. Int J Cardiol. 2015;201:288–90.

  7. 7.

    Grond-Ginsbach C, Debette S, Pezzini A. Genetic approaches in the study of risk factors for cervical artery dissection. Front Neurol Neurosci. 2005;20:30–43.

  8. 8.

    Pezzini A, Del Zotto E, Archetti S, Negrini R, Bani P, Albertini A, et al. Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke. 2002;33:664–9.

  9. 9.

    Longoni M, Grond-Ginsbach C, Grau AJ, Genius J, Debette S, Schwaninger M, et al. The ICAM-1 E469K gene polymorphism is a risk factor for spontaneous cervical artery dissection. Neurology. 2006;66:1273–5.

  10. 10.

    Debette S, Kamatani Y, Metso TM, Kloss M, Chauhan G, Engelter ST, et al. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nat Genet. 2015;47:78–83.

  11. 11.

    Makrygiannis G, Loeys B, Defraigne JO, Sakalihasan N. Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers-Danlos syndrome. Eur J Med Genet. 2015;58:634–6.

  12. 12.

    Grond-Ginsbach C, Brandt T, Kloss M, Aksay SS, Lyrer P, Traenka C, et al. Next generation sequencing analysis of patients with familial cervical artery dissection. Eur Stroke J. 2017;2:137–43.

  13. 13.

    Zhang Y, Tian Z, Sui B, Wang Y, Liu J, Li M, et al. Endovascular treatment of spontaneous intracranial fusiform and dissecting aneurysms: outcomes related to imaging classification of 309 cases. World Neurosurg. 2017;98:444–55.

  14. 14.

    Lee B, Vitale E, Superti-Furga A, Steinmann B, Ramirez F. G to T transversion at position +5 of a splice donor site causes skipping of the preceding exon in the type III procollagen transcripts of a patient with Ehlers-Danlos syndrome type IV. J Biol Chem. 1991;266:5256–9.

  15. 15.

    Sakai H, Suzuki S, Mizuguchi T, Imoto K, Yamashita Y, Doi H, et al. Rapid detection of gene mutations responsible for non-syndromic aortic aneurysm and dissection using two different methods: resequencing microarray technology and next-generation sequencing. Hum Genet. 2012;131:591–9.

  16. 16.

    Pickup MJ, Pollanen MS. Traumatic subarachnoid hemorrhage and the COL3A1 gene: emergence of a potential causal link. Forensic Sci Med Pathol. 2011;7:192–7.

  17. 17.

    Hung CC, Lin SY, Lee CN, Cheng HY, Lin SP, Chen MR, et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009;73:559–67.

  18. 18.

    Conibear E, Stevens TH. Vps52p, Vps53p, and Vps54p form a novel multisubunit complex required for protein sorting at the yeast late Golgi. Mol Biol Cell. 2000;11:305–23.

  19. 19.

    Sugimoto M, Kondo M, Hirose M, Suzuki M, Mekada K, Abe T, et al. Molecular identification of t(w5): Vps52 promotes pluripotential cell differentiation through cell-cell interactions. Cell Rep. 2012;2:1363–74.

  20. 20.

    Herskovits AZ, Davies P. Cloning and expression analysis of two novel PCTAIRE 3 transcripts from human brain. Gene. 2004;328:59–67.

  21. 21.

    Pirot N, Deleuze V, El-Hajj R, Dohet C, Sablitzky F, Couttet P, et al. LYL1 activity is required for the maturation of newly formed blood vessels in adulthood. Blood. 2010;115:5270–9.

  22. 22.

    Morrison AR, Yarovinsky TO, Young BD, Moraes F, Ross TD, Ceneri N, et al. Chemokine-coupled beta2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J Exp Med. 2014;211:1957–68.

  23. 23.

    Kelley MJ, Jawien W, Ortel TL, Korczak JF. Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nat Genet. 2000;26:106–8.

  24. 24.

    Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, et al. Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Thromb Haemost. 2010;103:826–32.

  25. 25.

    Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345:1167–75.

  26. 26.

    Grond-Ginsbach C, Debette S. The association of connective tissue disorders with cervical artery dissections. Curr Mol Med. 2009;9:210–4.

  27. 27.

    Debette S, Germain DP. Neurologic manifestations of inherited disorders of connective tissue. Handb Clin Neurol. 2014;119:565–76.

  28. 28.

    Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Clan genomics and the complex architecture of human disease. Cell. 2011;147:32–43.

  29. 29.

    Hayashi T, Tanimoto K, Hirayama-Yamada K, Tsuda E, Ayusawa M, Nunoda S, et al. Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy. J Hum Genet 2018;63:989–96.

  30. 30.

    Gbadegesin RA, Brophy PD, Adeyemo A, Hall G, Gupta IR, Hains D, et al. TNXB mutations can cause vesicoureteral reflux. J Am Soc Nephrol. 2013;24:1313–22.

  31. 31.

    Alcaraz LB, Exposito JY, Chuvin N, Pommier RM, Cluzel C, Martel S, et al. Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-beta. J Cell Biol. 2014;205:409–28.

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James R Lupski (Baylor College of Medicine) and Jennifer Posey (Baylor College of Medicine) assisted with organizing the study and revision of the manuscript. We thank the families who participated in this research. We also thank GeneSeeq Inc. for the technical support of whole-exome sequencing.

Author contributions

NW, XY, and PL conceived the project and designed the study. KW, QZ, XD, Jian Liu, XL, YZ, WC, and YN collected the cohorts. Sen Zhao, NW, PL, KW, QZ, MS, KA, JY, Jiachen Lin, and Bowen Liu analyzed the data. XS, YZ, YS, and ZY conducted the bioinformatic analysis. RD, Jiaqi Liu, BL, and BY helped with data interpretation and revised the manuscript. ZW, JS, and Shuyang Zhang helped in organizing the study and revising the manuscript. Sen Zhao, NW, KW, and PL wrote the manuscript.


Funding for this study was provided by grant no. 2016YFC1300800 from the National Key Research and Development Plan of China, nos. 81471167, 81671139, 81220108007, and no. 2014-1-1071 from the Special Research Project for Capital Health Development (all to Dr. Xinjian Yang), grant no. 81501852 from the National Natural Science Foundation of China; 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, no. 7172175 from the Beijing Natural Science Foundation, no. Z161100004916123 from the Beijing nova program, no. xxjc201717 from the Beijing nova program interdisciplinary collaborative project, no. 2016ZX310177 from the Central Level Public Interest Program for Scientific Research Institute, no. 3332016006 from the PUMC Youth Fund & the Fundamental Research Funds for the Central Universities, no. 2016-I2M-3-003 from the CAMS Initiative for Innovative Medicine, no. JQ201506 from the Distinguished Youth foundation of Peking Union Medical College Hospital (all to Dr. Nan Wu), and nos. 2016-I2M-2-006 and 2017-I2M-2-001 from the CAMS Initiative for Innovative Medicine (to Dr. Zhihong Wu).

Author information

Correspondence to Nan Wu or Pengfei Liu or Xinjian Yang.

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This study was approved by the ethics committee of Beijing Tiantan Hospital. Informed consent was obtained from each patient or their parents.

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The authors declare that they have no conflict of interest.

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