, Volume 8, Issue 2, pp 149–153 | Cite as

Large germline deletions and duplication in isolated cerebral cavernous malformation patients

  • U. Felbor
  • S. Gaetzner
  • D. J. Verlaan
  • R. Vijzelaar
  • G. A. Rouleau
  • A. M. Siegel
Short Communication


Cerebral cavernous malformations (CCM) are vascular lesions that predispose to headaches, seizures, and hemorrhagic stroke. Hereditary CCMs are usually associated with the occurrence of multiple CCMs and occur with a frequency of 1:2,000 to 1:10,000. In this study, eight isolated cases with multiple CCMs but no CCM1-3 point mutation were analyzed using the multiplex ligation-dependent probe amplification assay. Four genomic rearrangements were identified including a previously unreported large duplication within the CCM1 gene and a novel deletion involving the entire coding region of the CCM2 gene. Consequently, systematic screening for CCM deletions/duplications is recommended.


Vascular malformations Cerebral cavernous malformation MLPA Deletion Duplication 



The authors thank the patients for their cooperation. Ute Felbor receives an Emmy Noether grant from the Deutsche Forschungsgemeinschaft (Fe 432/6–5) and is supported by a grant from the Bavarian Genome Network. The experiments comply with the current German laws.

Disclosure The authors have reported no conflicts of interest.


  1. 1.
    Raychaudhuri R, Batjer HH, Awad IA (2005) Intracranial cavernous angioma: a practical review of clinical and biological aspects. Surg Neurol 63:319–328PubMedCrossRefGoogle Scholar
  2. 2.
    Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E (2006) Genotype–phenotype correlations in cerebral cavernous malformations patients. Ann Neurol 60:550–556PubMedCrossRefGoogle Scholar
  3. 3.
    Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E (2004) Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74:326–337PubMedCrossRefGoogle Scholar
  4. 4.
    Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacuet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42–51PubMedCrossRefGoogle Scholar
  5. 5.
    Gaetzner S, Stahl S, Sürücü O, Schaafhausen A, Halliger-Keller B, Bertalanffy H, Sure U, Felbor U (2006) CCM1 gene deletion identified by MLPA in cerebral cavernous malformation. Neurosurg Rev (in press) doi:10.1007/s10143-006-0057-1
  6. 6.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57PubMedCrossRefGoogle Scholar
  7. 7.
    Verlaan DJ, Laurent SB, Sure U, Bertalanffy H, Andermann E, Andermann F, Rouleau GA, Siegel AM (2004) CCM1 mutation screen of sporadic cases with cerebral cavernous malformations. Neurology 62:1213–1215PubMedGoogle Scholar
  8. 8.
    Verlaan DJ, Laurent SB, Rouleau GA, Siegel AM (2004) No CCM2 mutations in a cohort of 31 sporadic cases. Neurology 63:1979PubMedGoogle Scholar
  9. 9.
    Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E (1998) Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Lancet 352:1892–1897PubMedCrossRefGoogle Scholar
  10. 10.
    Liquori CL, Berg MJ, Squitieri F, Ottenbacher M, Sorlie M, Leedom TP, Cannella M, Maglione V, Ptacek L, Johnson EW, Marchuk DA (2006) Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27:118PubMedCrossRefGoogle Scholar
  11. 11.
    Lucas M, Costa AF, Montori M, Solano F, Zayas MD, Izquierdo G (2001) Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations. Ann Neurol 49:529–532PubMedCrossRefGoogle Scholar
  12. 12.
    Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville JP, Lescoat C, Cecillon M, Marechal E, Joutel A, Bach J-F, Tournier-Lasserve E (1999) Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:189–193PubMedCrossRefGoogle Scholar
  13. 13.
    Felbor U, Sure U, Grimm T, Bertalanffy H (2006) Genetics of cerebral cavernous angioma. Zentralbl Neurochir 67:1–7CrossRefGoogle Scholar
  14. 14.
    Shaw CJ, Lupski JR (2005) Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Hum Genet 116:1–7PubMedCrossRefGoogle Scholar
  15. 15.
    Lieber MR, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4:712–720PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • U. Felbor
    • 1
  • S. Gaetzner
    • 1
  • D. J. Verlaan
    • 2
  • R. Vijzelaar
    • 3
  • G. A. Rouleau
    • 2
  • A. M. Siegel
    • 4
  1. 1.Department of Human GeneticsUniversity of WürzburgWürzburgGermany
  2. 2.Centre de recherche du CHUM, Hôpital Notre-DameUniversity of MontrealQuebecCanada
  3. 3.MRC-HollandAmsterdamThe Netherlands
  4. 4.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland

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