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Neurogenetics

, Volume 9, Issue 1, pp 25–31 | Cite as

Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts

  • Christina L. Liquori
  • Silvana Penco
  • Judith Gault
  • Tracey P. Leedom
  • Laura Tassi
  • Teresa Esposito
  • Issam A. Awad
  • Luigi Frati
  • Eric W. Johnson
  • Ferdinando Squitieri
  • Douglas A. Marchuk
  • Fernando Gianfrancesco
Original Article

Abstract

Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in hemorrhagic stroke and seizures. Familial forms of CCM are inherited in an autosomal-dominant fashion, and three CCM genes have been identified. We recently determined that large genomic deletions in the CCM2 gene represent 22% of mutations in a large CCM cohort from the USA. In particular, a 77.6 kb deletion spanning CCM2 exons 2–10 displays an identical recombination event in eight CCM probands/families and appears to be common in the US population. In the current study, we report the identification of six additional probands/families from the USA with this same large deletion. Haplotype analysis strongly suggests that this common deletion derives from an ancestral founder. We also examined an Italian CCM cohort consisting of 24 probands/families who tested negative for mutations in the CCM1, CCM2, and CCM3 genes by DNA sequence analysis. Surprisingly, the common CCM2 deletion spanning exons 2–10 is not present in this population. Further analysis of the Italian cohort by multiplex ligation-dependent probe analysis identified a total of ten deletions and one duplication. The overall spectrum of genomic rearrangements in the Italian cohort is thus quite different than that seen in a US cohort. These results suggest that there are elements within all three of the CCM genes that predispose them to large deletion/duplication events but that the common deletion spanning CCM2 exons 2–10 appears to be specific to the US population due to a founder effect.

Keywords

Genomic deletions Cerebral cavernous malformations CCM probands 

Notes

Acknowledgments

We are grateful to the CCM patients and their families for participation in this study. This work was supported by NIH grant NS43543 to D.A.M.; NRSA grant 1 F32 NS51082-03 to C.L.L.; Italian National Research Council Short-term Mobility Program to F.G.; Lega Italiana Contro l’Epilessia grant to S.P. and Italian Health Ministry COFIN grant to F.S. The financial support of Telethon-Italy (Grant No. GGP07170) is gratefully acknowledged.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Christina L. Liquori
    • 1
  • Silvana Penco
    • 2
  • Judith Gault
    • 3
  • Tracey P. Leedom
    • 1
  • Laura Tassi
    • 4
  • Teresa Esposito
    • 5
    • 6
  • Issam A. Awad
    • 7
  • Luigi Frati
    • 6
    • 8
  • Eric W. Johnson
    • 9
  • Ferdinando Squitieri
    • 6
  • Douglas A. Marchuk
    • 1
  • Fernando Gianfrancesco
    • 5
    • 6
  1. 1.Department of Molecular Genetics and MicrobiologyDuke University Medical CenterDurhamUSA
  2. 2.Department of Laboratory Medicine, Medical GeneticsA. O. Niguarda Ca’ Granda HospitalMilanItaly
  3. 3.Department of NeurosurgeryUniversity of Colorado Health Sciences CenterDenverUSA
  4. 4.Department of NeuroscienceRegional Centre for Epilepsy Surgery; Niguarda Ca’ Granda HospitalMilanItaly
  5. 5.Institute of Genetics and Biophysics“Adriano Buzzati Traverso”, Italian National Research CouncilNaplesItaly
  6. 6.Neurogenetics UnitIRCCS NeuromedPozzilliItaly
  7. 7.Department of Neurological SurgeryNorthwestern University Feinberg School of Medicine, Evanston Northwestern HealthcareEvanstonUSA
  8. 8.Department of Experimental MedicineUniversity La SapienzaRomeItaly
  9. 9.Molecular Diagnostics and Biobanking, Prevention GeneticsMarshfieldUSA

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