Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genetics of brain arteriovenous malformations and cerebral cavernous malformations

Journal of Human Genetics volume 68, pages 157–167 (2023)Cite this article

Subjects

Abstract

Cerebrovascular malformations comprise abnormal development of cerebral vasculature. They can result in hemorrhagic stroke due to rupture of lesions as well as seizures and neurological defects. The most common forms of cerebrovascular malformations are brain arteriovenous malformations (bAVMs) and cerebral cavernous malformations (CCMs). They occur in both sporadic and inherited forms. Rapidly evolving molecular genetic methodologies have helped to identify causative or associated genes involved in genesis of bAVMs and CCMs. In this review, we highlight the current knowledge regarding the genetic basis of these malformations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Scimone C, Donato L, Marino S, Alafaci C, D’Angelo R, Sidoti A. Vis-a-vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis. Neurol Sci. 2019;40:243–51.

    Article  Google Scholar 

  2. Venugopal V, Sumi S. Molecular biomarkers and drug targets in brain arteriovenous and cavernous malformations: where are we? Stroke. 2022;53:279–89.

    Article  Google Scholar 

  3. Zafar A, Fiani B, Hadi H, Arshad M, Cathel A, Naeem M, et al. Cerebral vascular malformations and their imaging modalities. Neurol Sci. 2020;41:2407–21.

    Article  Google Scholar 

  4. Whitehead KJ, Smith MC, Li DY. Arteriovenous malformations and other vascular malformation syndromes. Cold Spring Harb Perspect Med. 2013;3:a006635.

    Article  Google Scholar 

  5. Solomon RA, Connolly ES Jr. Arteriovenous malformations of the brain. N. Engl J Med. 2017;376:1859–66.

    Article  Google Scholar 

  6. Gao S, Nelson J, Weinsheimer S, Winkler EA, Rutledge C, Abla AA, et al. Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype. J Neurosurg. 2022;136:148–55.

    Article  CAS  Google Scholar 

  7. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg. 2013;118:437–43.

    Article  Google Scholar 

  8. Al-Shahi Salman R. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001;124:1900–26.

    Article  Google Scholar 

  9. Derdeyn CP, Zipfel GJ, Albuquerque FC, Cooke DL, Feldmann E, Sheehan JP, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48:e200–e24.

    Article  Google Scholar 

  10. McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1.

    Article  Google Scholar 

  11. Guttmacher AE. Hereditary hemorrhagic telangiectasia. N. Engl J Med. 1995;333:918–24.

    Article  CAS  Google Scholar 

  12. Snodgrass RO, Chico TJA, Arthur HM. Hereditary haemorrhagic telangiectasia, an inherited vascular disorder in need of improved evidence-based pharmaceutical interventions. Genes (Basel). 2021;12:174.

    Article  CAS  Google Scholar 

  13. Nishida T, Faughnan ME, Krings T, Chakinala M, Gossage JR, Young WL, et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012;158A:2829–34.

    Article  Google Scholar 

  14. Lam S, Guthrie KS, Latif MA, Weiss CR. Genetic counseling and testing for hereditary hemorrhagic telangiectasia. Clin Genet. 2022;101:275–84.

    Article  CAS  Google Scholar 

  15. Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010;128:61–77.

    Article  CAS  Google Scholar 

  16. Brinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127:302–10.

    Article  Google Scholar 

  17. Villa D, Cinnante C, Valcamonica G, Manenti G, Lanfranconi S, Colombi A, et al. Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG. BMC Neurol. 2020;20:316.

    Article  Google Scholar 

  18. Palagallo GJ, McWilliams SR, Sekarski LA, Sharma A, Goyal MS, White AJ. The prevalence of malformations of cortical development in a pediatric hereditary hemorrhagic telangiectasia population. AJNR Am J Neuroradiol. 2017;38:383–86.

    Article  CAS  Google Scholar 

  19. Klostranec JM, Chen L, Mathur S, McDonald J, Faughnan ME, Ratjen F, et al. A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology. 2019;92:34–42.

    Article  Google Scholar 

  20. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17:860–71.

    Article  CAS  Google Scholar 

  21. AAssar OS, Friedman CM, White RI Jr. The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 1991;101:977–80.

  22. Berg J, Porteous M, Reinhardt D, Gallione C, Holloway S, Umasunthar T, et al. Hereditary haemorrhagic telangiectasia a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003;40:585–90.

    Article  CAS  Google Scholar 

  23. Morgan T, McDonald J, Anderson C, Ismail M, Miller F, Mao R, et al. Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu Syndrome). Pediatrics. 2002;109:E12.

    Article  Google Scholar 

  24. McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011;13:607–16.

    Article  Google Scholar 

  25. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–51.

    Article  CAS  Google Scholar 

  26. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, et al. Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.

    Article  CAS  Google Scholar 

  27. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852–59.

    Article  CAS  Google Scholar 

  28. Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006;140:463–70.

    Article  Google Scholar 

  29. Bernabeu C, Bayrak-Toydemir P, McDonald J, Letarte M. Potential second-hits in hereditary hemorrhagic telangiectasia. J Clin Med. 2020;9:3571.

    Article  CAS  Google Scholar 

  30. Sánchez-Martínez R, Iriarte A, María Mora-Luján J, Luis Patier J, López-Wolf D, Ojeda. A. Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet J Rare Dis. 2020;15:138.

    Article  Google Scholar 

  31. McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011;79:335–44.

    Article  CAS  Google Scholar 

  32. Damjanovich K. 5’UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011;6:85.

    Article  Google Scholar 

  33. Albiñana V, Zafra MP, Colau J, Zarrabeitia R, Recio-Poveda L, Olavarrieta L, et al. Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1. BMC Med Genet. 2017;18:20.

    Article  Google Scholar 

  34. Wooderchak-Donahue W. Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. J Med Genet. 2018;55:824–30.

    Article  CAS  Google Scholar 

  35. Lesca G, Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004;23:289–99.

    Article  CAS  Google Scholar 

  36. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110.

    Article  CAS  Google Scholar 

  37. Gedge F, McDonald J, Phansalkar A, Chou LS, Calderon F, Mao R, et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007;9:258–65.

    Article  CAS  Google Scholar 

  38. Best DH, Vaughn C, McDonald J, Damjanovich K, Runo JR, Chibuk JM, et al. Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. J Med Genet. 2011;48:358–60.

    Article  CAS  Google Scholar 

  39. Clarke JM, Alikian M, Xiao S, Kasperaviciute D, Thomas E, Turbin I, et al. Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline. J Med Genet. 2020;57:859–62.

    Article  Google Scholar 

  40. Torring PM, Kjeldsen AD, Ousager LB, Brusgaard K. ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia. Mol Genet Genom Med. 2018;6:121–25.

    Article  CAS  Google Scholar 

  41. McDonald J, Wooderchak-Donahue WL, Henderson K, Paul E, Morris A, Bayrak-Toydemir. P. Tissue-specific mosaicism in hereditary hemorrhagic telangiectasia: Implications for genetic testing in families. Am J Med Genet A. 2018;176:1618–21.

    Article  CAS  Google Scholar 

  42. Latif MA. Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia: Experience from an HHT Center of Excellence. Am J Med Genet A. 2021;185:1981–90.

    Article  CAS  Google Scholar 

  43. Wain KE, Ellingson MS, McDonald J, Gammon A, Roberts M, Pichurin P, et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med. 2014;16:588–93.

    Article  CAS  Google Scholar 

  44. Aagaard-Kienitz B. Chromosomal translocation disrupting the SMAD4 gene resulting in the combined phenotype of Juvenile polyposis syndrome and Hereditary Hemorrhagic Telangiectasia. Mol Genet Genom Med. 2020;8:e1498.

    Google Scholar 

  45. Vorselaars VMM, Diederik A, Prabhudesai V, Velthuis S, Vos JA, Snijder RJ, et al. SMAD4 gene mutation increases the risk ofaortic dilation in patients with hereditary haemorrhagic telangiectasia. Int J Cardiol. 2017;245:114–8.

    Article  CAS  Google Scholar 

  46. Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43:793–7.

    Article  CAS  Google Scholar 

  47. Lesca G, Burnichon N, Raux G, Tosi M, Pinson S, Marion MJ, et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006;27:598.

    Article  Google Scholar 

  48. Prigoda NL, Savas S, Abdalla SA, Piovesan B, Rushlow D, Vandezande K, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet. 2006;43:722–8.

    Article  CAS  Google Scholar 

  49. Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010;152A:333–9.

    Article  CAS  Google Scholar 

  50. Wooderchak-Donahue WL, McDonald J, O’Fallon B, Upton PD, Li W, Roman BL, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93:530–7.

    Article  CAS  Google Scholar 

  51. Hodgson J, Ruiz-Llorente L, McDonald J, Quarrell O, Ugonna K, Bentham J, et al. Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT-like” syndrome in children. Mol Genet Genom Med. 2021;9:e1685.

    CAS  Google Scholar 

  52. Balachandar S, Graves TJ, Shimonty A, Kerr K, Kilner J, Xiao S, et al. Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Am J Med Genet A. 2022;188:959–64.

    Article  CAS  Google Scholar 

  53. Farhan A, Yuan F, Partan E, Weiss. CR. Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5. Am J Med Genet A. 2022;188:199–209.

    Article  CAS  Google Scholar 

  54. Ola R, Kunzel SH, Zhang F, Genet G, Chakraborty R, Pibouin-Fragner L, et al. SMAD4 prevents flow induced arteriovenous malformations by inhibiting casein kinase 2. Circulation. 2018;138:2379–94.

    Article  CAS  Google Scholar 

  55. Pece N, Vera S, Cymerman U, White RI Jr., Wrana JL, Letarte M. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Invest. 1997;100:2568–79.

    Article  CAS  Google Scholar 

  56. Abdalla SA. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000;9:1227–37.

    Article  CAS  Google Scholar 

  57. Snellings DA, Gallione CJ, Clark DS, Vozoris NT, Faughnan ME, Marchuk DA. Somatic mutations in vascular malformations of hereditary hemorrhagic telangiectasia result in bi-allelic loss of ENG or ACVRL1. Am J Hum Genet. 2019;105:894–906.

    Article  CAS  Google Scholar 

  58. Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990;265:8361–64.

    Article  CAS  Google Scholar 

  59. Lopez-Novoa JM, Bernabeu C. The physiological role of endoglin in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2010;299:H959–74.

    Article  CAS  Google Scholar 

  60. Campioni D, Zauli G, Gambetti S, Campo G, Cuneo A, Ferrari R, et al. In vitro characterization of circulating endothelial progenitor cells isolated from patients with acute coronary syndrome. PLoS One. 2013;8:e56377.

    Article  CAS  Google Scholar 

  61. Rossi E, Bernabeu C, Smadja DM. Endoglin as an adhesion molecule in mature and progenitor endothelial cells: a function beyond TGF-beta. Front Med (Lausanne). 2019;6:10.

    Article  Google Scholar 

  62. Bourdeau A, Faughnan ME, Letarte M. Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia. Trends Cardiovasc Med. 2000;10:279–85.

    Article  CAS  Google Scholar 

  63. Tual-Chalot S, Oh SP, Arthur HM. Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. Front Genet. 2015;6:25.

    Article  Google Scholar 

  64. Ruiz-Llorente L, Gallardo-Vara E, Rossi E, Smadja DM, Botella LM, Bernabeu C. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets. 2017;21:933–47.

    Article  CAS  Google Scholar 

  65. Salmon RM, Guo J, Wood JH, Tong Z, Beech JS, Lawera A, et al. Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Nat Commun. 2020;11:1621.

    Article  CAS  Google Scholar 

  66. Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, et al. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 2012;119:6162–71.

    Article  CAS  Google Scholar 

  67. Chen H, Shi S, Acosta L, Li W, Lu J, Bao S, et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 2004;131:2219–31.

    Article  CAS  Google Scholar 

  68. David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953–61.

    Article  CAS  Google Scholar 

  69. Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci. 2007;120:964–72.

    Article  CAS  Google Scholar 

  70. Castonguay R, Werner ED, Matthews RG, Presman E, Mulivor AW, Solban N, et al. Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. J Biol Chem. 2011;286:30034–46.

    Article  CAS  Google Scholar 

  71. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet. 2000;26:328–31.

    Article  CAS  Google Scholar 

  72. Li. Defective angiogenesis in mice lacking endoglin. Science. 1999;284:1534–7.

  73. Kim YH, Choe SW, Chae MY, Hong S, Oh SP. SMAD4 deficiency leads to development of arteriovenous malformations in neonatal and adult mice. J Am Heart Assoc. 2018;7:e009514.

    Article  CAS  Google Scholar 

  74. Ruiz S, Zhao H, Chandakkar P, Chatterjee PK, Papoin J, Blanc L, et al. A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci Rep. 2016;5:37366.

    Article  Google Scholar 

  75. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240–9.

    Article  CAS  Google Scholar 

  76. Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15:265–9.

    Article  CAS  Google Scholar 

  77. Larralde M, Abad ME, Luna PC, Hoffner. MV. Capillary malformation–arteriovenous malformation a clinical review of 45 patients. Int J Dermatol. 2014;53:458–61.

    Article  Google Scholar 

  78. Valdivielso-Ramos M, Martin-Santiago A, Azana JM, Hernandez-Nunez A, Vera A, Perez B, et al. Capillary malformation-arteriovenous malformation syndrome: a multicentre study. Clin Exp Dermatol. 2021;46:300–05.

    Article  CAS  Google Scholar 

  79. Revencu N, Fastre E, Ravoet M, Helaers R, Brouillard P, Bisdorff-Bresson A, et al. RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation. J Med Genet. 2020;57:48–52.

    Article  CAS  Google Scholar 

  80. Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34:1632–41.

    Article  CAS  Google Scholar 

  81. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29:959–65.

    Article  CAS  Google Scholar 

  82. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136:1037–48.

    Article  CAS  Google Scholar 

  83. Edwards LR, Blechman AB, Zlotoff BJ. RASA1 mutation in a family with capillary malformation-arteriovenous malformation syndrome: A discussion of the differential diagnosis. Pediatr Dermatol. 2018;35:e9–e12.

    Article  Google Scholar 

  84. Wooderchak-Donahue WL, Johnson P, McDonald J, Blei F, Berenstein A, Sorscher M, et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet. 2018;26:1521–36.

    Article  CAS  Google Scholar 

  85. Gordo G, Rodriguez-Laguna L, Agra N, Mendez P, Feito M, Lapunzina P, et al. Constitutional mosaicism in RASA1-related capillary malformation-arteriovenous malformation. Clin Genet. 2019;95:516–19.

    Article  CAS  Google Scholar 

  86. Vivanti A, Ozanne A, Grondin C, Saliou G, Quevarec L, Maurey H, et al. Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain. 2018;141:979–88.

    Article  Google Scholar 

  87. Wooderchak-Donahue WL, Akay G, Whitehead K, Briggs E, Stevenson DA, O’Fallon B, et al. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genet Med. 2019;21:2007–14.

    Article  Google Scholar 

  88. Chen D, Hughes ED, Saunders TL, Wu J, Hernandez Vasquez MN, Makinen T, et al. Angiogenesis depends upon EPHB4-mediated export of collagen IV from vascular endothelial cells. JCI Insight. 2022;7:e156928.

    Article  Google Scholar 

  89. Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, Le J, Wallenstein MB, Milla C, et al. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A. 2016;170:1450–4.

    Article  CAS  Google Scholar 

  90. Lapinski PE, Doosti A, Salato V, North P, Burrows PE, King PD. Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet. 2018;61:11–16.

    Article  Google Scholar 

  91. Gasper R, Wittinghofer F. The Ras switch in structural and historical perspective. Biol Chem. 2019;401:143–63.

    Article  Google Scholar 

  92. King PD. Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis. Sci Signal. 2013;6:re1.

    Article  Google Scholar 

  93. Wang HU, Chen ZF, Anderson. DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell. 1998;93:741–53.

    Article  CAS  Google Scholar 

  94. Bai J, Wang YJ, Liu L, Zhao YL. Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res. 2014;42:405–15.

    Article  Google Scholar 

  95. Lin FJ, Tsai MJ, Tsai SY. Artery and vein formation: a tug of war between different forces. EMBO Rep. 2007;8:920–4.

    Article  CAS  Google Scholar 

  96. Kaenel P, Hahnewald S, Wotzkow C, Strange R, Andres AC. Overexpression of EphB4 in the mammary epithelium shifts the differentiation pathway of progenitor cells and promotes branching activity and vascularization. Dev Growth Differ. 2014;56:255–75.

    Article  CAS  Google Scholar 

  97. Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, et al. Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein. Nature. 1995;377:695–701.

    Article  CAS  Google Scholar 

  98. Gerety SS, Wang HU, Chen ZF, Anderson DJ. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell. 1999;4:403–14.

    Article  CAS  Google Scholar 

  99. Queisser A, Boon LM, Vikkula M. Etiology and genetics of congenital vascular lesions. Otolaryngol Clin North Am. 2018;51:41–53.

    Article  Google Scholar 

  100. Pawlikowska L, Tran MN, Achrol AS, Ha C, Burchard E, Choudhry S, et al. Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke. 2005;36:2278–80.

    Article  CAS  Google Scholar 

  101. Kim H, Hysi PG, Pawlikowska L, Choudhry S, Gonzalez Burchard E, Kwok PY, et al. Population stratification in a case-control study of brain arteriovenous malformation in Latinos. Neuroepidemiology. 2008;31:224–8.

    Article  Google Scholar 

  102. Kim H, Hysi PG, Pawlikowska L, Poon A, Burchard EG, Zaroff JG, et al. Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis. 2009;27:176–82.

    Article  CAS  Google Scholar 

  103. Zhao Y, Li P, Fan W, Chen D, Gu Y, Lu D, et al. The rs522616 polymorphism in the matrix metalloproteinase-3 (MMP-3) gene is associated with sporadic brain arteriovenous malformation in a Chinese population. J Clin Neurosci. 2010;17:1568–72.

    Article  CAS  Google Scholar 

  104. Chen H, Gu Y, Wu W, Chen D, Li P, Fan W, et al. Polymorphisms of the vascular endothelial growth factor A gene and susceptibility to sporadic brain arteriovenous malformation in a Chinese population. J Clin Neurosci. 2011;18:549–53.

    Article  CAS  Google Scholar 

  105. Jiang N, Li X, Qi T, Guo S, Liang F, Huang Z. Susceptible gene single nucleotide polymorphism and hemorrhage risk in patients with brain arteriovenous malformation. J Clin Neurosci. 2011;18:1279–81.

    Article  CAS  Google Scholar 

  106. Mikhak B, Weinsheimer S, Pawlikowska L, Poon A, Kwok PY, Lawton MT, et al. Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovasc Dis. 2011;31:338–45.

    Article  CAS  Google Scholar 

  107. Fontanella M, Rubino E, Crobeddu E, Gallone S, Gentile S, Garbossa D, et al. Brain arteriovenous malformations are associated with interleukin-1 cluster gene polymorphisms. Neurosurgery. 2012;70:12–7.

    Article  Google Scholar 

  108. Erkinova SA, Sokolova EA, Orlov KY, Kiselev VS, Strelnikov NV, Dubovoy AV, et al. Angiopoietin-like proteins 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformation. J Stroke Cerebrovasc Dis. 2018;27:908–13.

    Article  Google Scholar 

  109. Sturiale CL, Puca A, Sebastiani P, Gatto I, Albanese A, Di Rocco C, et al. Single nucleotide polymorphisms associated with sporadic brain arteriovenous malformations: where do we stand? Brain. 2013;136:665–81.

    Article  Google Scholar 

  110. Weinsheimer S, Bendjilali N, Nelson J, Guo DE, Zaroff JG, Sidney S, et al. Genome-wide association study of sporadic brain arteriovenous malformations. J Neurol Neurosurg Psychiatry. 2016;87:916–23.

    Article  Google Scholar 

  111. Li H, Nam Y, Huo R, Fu W, Jiang B, Zhou Q, et al. De novo germline and somatic variants convergently promote endothelial-to-mesenchymal transition in simplex brain arteriovenous malformation. Circ Res. 2021;129:825–39.

    Article  CAS  Google Scholar 

  112. Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N. Engl J Med. 2018;378:250–61.

    Article  CAS  Google Scholar 

  113. Hong T, Yan Y, Li J, Radovanovic I, Ma X, Shao YW, et al. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain. 2019;142:23–34.

    Article  Google Scholar 

  114. Priemer DS, Vortmeyer AO, Zhang S, Chang HY, Curless KL, Cheng L. Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation. Hum Pathol. 2019;89:33–9.

    Article  CAS  Google Scholar 

  115. Goss JA, Huang AY, Smith E, Konczyk DJ, Smits PJ, Sudduth CL, et al. Somatic mutations in intracranial arteriovenous malformations. PLoS One. 2019;14:e0226852.

    Article  CAS  Google Scholar 

  116. Oka M, Kushamae M, Aoki T, Yamaguchi T, Kitazato K, Abekura Y, et al. KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg. 2019;126:e1365–e73.

    Article  Google Scholar 

  117. Bameri O, Salarzaei M, Parooie F. KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis. Inter Neuroradiol. 2021;27:539–46.

    Article  Google Scholar 

  118. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33.

    Article  CAS  Google Scholar 

  119. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263–84.

    Article  CAS  Google Scholar 

  120. Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22:4456–62.

    Article  CAS  Google Scholar 

  121. Meadows KN, Bryant P, Pumiglia K. Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem. 2001;276:49289–98.

    Article  CAS  Google Scholar 

  122. Hong CC, Peterson QP, Hong JY, Peterson RT. Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling. Curr Biol. 2006;16:1366–72.

    Article  CAS  Google Scholar 

  123. Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D, et al. Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res. 2020;127:727–43.

    Article  CAS  Google Scholar 

  124. Park ES, Kim S, Huang S, Yoo JY, Korbelin J, Lee TJ, et al. Selective endothelial hyperactivation of oncogenic KRAS induces brain arteriovenous malformations in mice. Ann Neurol. 2021;89:926–41.

    Article  CAS  Google Scholar 

  125. Clatterbuck RE, Eberhart CG, Crain BJ, Rigamonti D. Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry. 2001;71:188–92.

    Article  CAS  Google Scholar 

  126. Morris Z, Whiteley WN, Longstreth WT Jr., Weber F, Lee YC, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016.

    Article  Google Scholar 

  127. Al-Holou WN, O’Lynnger TM, Pandey AS, Gemmete JJ, Thompson BG, Muraszko KM, et al. Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr. 2012;9:198–205.

    Article  Google Scholar 

  128. Moore SA, Brown RD Jr., Christianson TJ, Flemming KD. Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort. J Neurosurg. 2014;120:1188–92.

    Article  Google Scholar 

  129. Salman RA-S, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, et al. Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol. 2012;11:217–24.

    Article  Google Scholar 

  130. Karschnia P, Nishimura S, Louvi A. Cerebrovascular disorders associated with genetic lesions. Cell Mol Life Sci. 2019;76:283–300.

    Article  CAS  Google Scholar 

  131. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15:166–73.

    Article  Google Scholar 

  132. Akers A, Al-Shahi Salman R, Dahlem IAA, Flemming K, Hart B. et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery. 2017;80:665–80.

    Article  Google Scholar 

  133. Spiegler S, Rath M, Paperlein C, Felbor U. Cerebral cavernous malformations: an update on prevalence, molecular genetic analyses, and genetic counselling. Mol Syndromol. 2018;9:60–9.

    Article  CAS  Google Scholar 

  134. L-lC S. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. 1999;23:189–93.

    Article  Google Scholar 

  135. Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 2003;73:1459–64.

    Article  CAS  Google Scholar 

  136. Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005;76:42–51.

    Article  CAS  Google Scholar 

  137. Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ. Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet. 2012;20:134–40.

    Article  CAS  Google Scholar 

  138. Riant F, Odent S, Cecillon M, Pasquier L, de Barace C, Carney MP, et al. Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations. Clin Genet. 2014;86:585–8.

    Article  CAS  Google Scholar 

  139. Spiegler S, Rath M, Hoffjan S, Dammann P, Sure U, Pagenstecher A, et al. First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing. Neurogenetics. 2018;19:55–9.

    Article  CAS  Google Scholar 

  140. Much CD, Schwefel K, Skowronek D, Shoubash L, von Podewils F, Elbracht M, et al. Novel pathogenic variants in a cassette exon of CCM2 in patients with cerebral cavernous malformations. Front Neurol. 2019;10:1219.

    Article  Google Scholar 

  141. Grippaudo FR, Piane M, Amoroso M, Longo B, Penco S, Chessa L, et al. Cutaneous venous malformations related to KRIT1 mutation: case report and literature review. J Mol Neurosci. 2013;51:442–5.

    Article  CAS  Google Scholar 

  142. Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, et al. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann Neurol. 2006;60:550–6.

    Article  Google Scholar 

  143. Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, et al. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med. 2015;17:188–96.

    Article  CAS  Google Scholar 

  144. Snellings DA, Hong CC, Ren AA, Lopez-Ramirez MA, Girard R, Srinath A, et al. Cerebral cavernous malformation: from mechanism to therapy. Circ Res. 2021;129:195–215.

    Article  CAS  Google Scholar 

  145. Rinaldi C, Bramanti P, Scimone C, Donato L, Alafaci C, D’Angelo R, et al. Relevance of CCM gene polymorphisms for clinical management of sporadic cerebral cavernous malformations. J Neurol Sci. 2017;380:31–7.

    Article  CAS  Google Scholar 

  146. Gault J, Shenkar R, Recksiek P, Awad IA. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 2005;36:872–4.

    Article  Google Scholar 

  147. Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet. 2009;18:919–30.

    Article  CAS  Google Scholar 

  148. McDonald DA, Shi C, Shenkar R, Gallione CJ, Akers AL, Li S, et al. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis. Hum Mol Genet. 2014;23:4357–70.

    Article  CAS  Google Scholar 

  149. Hong T, Xiao X, Ren J, Cui B, Zong Y, Zou J, et al. Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations. Brain. 2021;144:2648–58.

    Article  Google Scholar 

  150. Peyre M, Miyagishima D, Bielle F, Chapon F, Sierant M, Venot Q, et al. Somatic PIK3CA mutations in sporadic cerebral cavernous malformations. N. Engl J Med. 2021;385:996.

    Article  CAS  Google Scholar 

  151. Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, et al. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature 2021;594:271–76.

    Article  CAS  Google Scholar 

  152. Weng J, Yang Y, Song D, Huo R, Li H, Chen Y, et al. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. Am J Hum Genet. 2021;108:942–50.

    Article  CAS  Google Scholar 

  153. Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, et al. CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet. 2005;14:2521–31.

    Article  CAS  Google Scholar 

  154. Voss K, Stahl S, Schleider E, Ullrich S, Nickel J, Mueller TD, et al. CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics. 2007;8:249–56.

    Article  CAS  Google Scholar 

  155. Mably JD, Chuang LP, Serluca FC, Mohideen MA, Chen JN, Fishman MC. santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development. 2006;133:3139–46.

    Article  CAS  Google Scholar 

  156. Hogan BM, Bussmann J, Wolburg H, Schulte-Merker S. ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Hum Mol Genet. 2008;17:2424–32.

    Article  CAS  Google Scholar 

  157. Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, et al. Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat Med. 2009;15:169–76.

    Article  CAS  Google Scholar 

  158. Zhou Z, Rawnsley DR, Goddard LM, Pan W, Cao XJ, Jakus Z, et al. The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression. Dev Cell. 2015;32:168–80.

    Article  CAS  Google Scholar 

  159. Boulday G, Blecon A, Petit N, Chareyre F, Garcia LA, Niwa-Kawakita M, et al. Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations. Dis Model Mech. 2009;2:168–77.

    Article  CAS  Google Scholar 

  160. Boulday G, Rudini N, Maddaluno L, Blecon A, Arnould M, Gaudric A, et al. Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J Exp Med. 2011;208:1835–47.

    Article  CAS  Google Scholar 

  161. Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 2017;545:305–10.

    Article  CAS  Google Scholar 

  162. Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, et al. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016;532:122–6.

    Article  CAS  Google Scholar 

  163. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. 2009;15:177–84.

    Article  CAS  Google Scholar 

  164. Borikova AL, Dibble CF, Sciaky N, Welch CM, Abell AN, Bencharit S, et al. Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J Biol Chem. 2010;285:11760–4.

    Article  CAS  Google Scholar 

  165. Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med. 2010;207:881–96.

    Article  CAS  Google Scholar 

  166. Zheng X, Xu C, Di Lorenzo A, Kleaveland B, Zou Z, Seiler C, et al. CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations. J Clin Invest. 2010;120:2795–804.

    Article  CAS  Google Scholar 

  167. McDonald DA, Shi C, Shenkar R, Stockton RA, Liu F, Ginsberg MH, et al. Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease. Stroke. 2012;43:571–4.

    Article  CAS  Google Scholar 

  168. Lopez-Ramirez M. Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice. Blood. 2019;133:193–204.

    Article  CAS  Google Scholar 

  169. Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, et al. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature. 2013;498:492–6.

    Article  CAS  Google Scholar 

  170. Limaye N, Kangas J, Mendola A, Godfraind C, Schlogel MJ, Helaers R, et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. 2015;97:914–21.

    Article  CAS  Google Scholar 

  171. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovee JV, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166:1048–54 e1-5.

    Article  CAS  Google Scholar 

  172. Rodriguez-Laguna L, Agra N, Ibanez K, Oliva-Molina G, Gordo G, Khurana N, et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J Exp Med. 2019;216:407–18.

    Article  CAS  Google Scholar 

  173. Ten Broek RW, Eijkelenboom A, van der Vleuten CJM, Kamping EJ, Kets M, Verhoeven BH, et al. Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases. Genes Chromosomes Cancer. 2019;58:541–50.

    Article  Google Scholar 

  174. Castel P, Carmona FJ, Grego-Bessa J, Berger MF, Viale A, Anderson. KV. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med. 2016;8:332ra42.

    Article  Google Scholar 

  175. Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, et al. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Sci Transl Med. 2016;8:332ra43.

    Article  Google Scholar 

  176. Couto JA, Vivero MP, Kozakewich HP, Taghinia AH, Mulliken JB, Warman ML, et al. A somatic MAP3K3 mutation is associated with verrucous venous malformation. Am J Hum Genet. 2015;96:480–6.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by a Grant-in-Aid for Scientific Research (B) (No. 21H03041) to Dr. Saito, a Grant-in-Aid for Scientific Research (C) (No. 19K09473) to Dr. Miyawaki, and a Grant-in-Aid for Research Activity Start-up (No. 21K20985) to Dr. Hongo from the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroki Hongo, Satoru Miyawaki, Yu Teranishi, Daiichiro Ishigami, Kenta Ohara, Yu Sakai, Motoyuki Umekawa, Satoshi Koizumi & Nobuhito Saito

  2. Department of Neurosurgery, Kyorin University, Tokyo, Japan

    Daisuke Shimada & Hirofumi Nakatomi

  3. Department of Neurosurgery, Fuji Brain Institute and Hospital, Shizuoka, Japan

    Hideaki Ono

Authors
  1. Hiroki Hongo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoru Miyawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Teranishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daiichiro Ishigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenta Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daisuke Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Motoyuki Umekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Satoshi Koizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideaki Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hirofumi Nakatomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nobuhito Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: HH, SM. Project administration: NS. Writing–original draft: HH. Writing–review and editing: SM, YT, DI, KO, YS, DS, MU, SK, HO, HN, NS.

Corresponding author

Correspondence to Satoru Miyawaki.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hongo, H., Miyawaki, S., Teranishi, Y. et al. Genetics of brain arteriovenous malformations and cerebral cavernous malformations. J Hum Genet 68, 157–167 (2023). https://doi.org/10.1038/s10038-022-01063-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-022-01063-8

This article is cited by

Search

Advanced search

Quick links