, Volume 14, Issue 2, pp 133–141 | Cite as

CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions

  • Florence RiantEmail author
  • Michaelle Cecillon
  • Pascale Saugier-Veber
  • Elisabeth Tournier-Lasserve
Original Article


Loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 gene are identified in about 95 % of familial cases of cerebral cavernous malformations and 2/3 of sporadic cases with multiple lesions. In this study, 279 consecutive index patients referred for either genetic counseling or for diagnosis of cerebral hemorrhage of unknown etiology were analyzed for the three cerebral cavernous malformations (CCM) genes by direct sequencing and quantitative studies, to characterize in more detail the mutation spectrum associated with cerebral cavernous malformations and to optimize CCM gene screening. Analysis of the cDNA was performed when possible to detect the consequences of the genomic variations. A pathogenic mutation was identified in 122 patients. CCM1 was mutated in 80 patients (65 %), CCM2 in 23 (19 %), and CCM3 in 19 (16 %). One hundred patients harbored a loss of function point mutation (82 %) and 22 had a large deletion (18 %). Novel unclassified variants were detected in the patients among whom six led to a splicing defect. The causality of three missense variants that did not modify the splicing could not be established. These findings expand the CCM mutation spectrum and highlight the importance of screening the three CCM genes with both direct sequencing and a quantitative method. In addition, six new unclassified variants were shown to be deleterious because they led to a splicing defect. This underlines the necessity of the cDNA analysis when an unknown variant is detected.


Cerebral cavernous malformations CCM KRIT1 MGC4607 PDCD10 Unclassified variants 



We thank the patients and the clinicians who referred the patients: K. Abel Lablanche, Y. Benkaci, S. Berroir, J.Y. Bignon, P. Bitoun, M.P. Brechard, B. Bussel, F. Cartault, JF. Cassarini, H. Chabriat, S. Chapuis, M. Clanet, P. Corcia, C. Coubes, F. Darcel, A. David, C. de la Rochebrochard, I. Delalande, X. Deplanque, L. Derex, I. Desguerre, O. Detante, F. Di Rocco, A. Dieux, B. Doray, V. Drouin-Garraud, C. Férec, H. Flodrops, C. Francannet, , E. Ginglinger, I. Gobron, O. Godefroy, B. Godet, C. Goizet, V. Golfier., L. Guyant Marechal, D. Hervé, M. Holder Espinasse, H. Hosseini, E. Jeandidier, P. Labauge, A. Landais, C. Laroche, B. Leheup, P. Lejeune, G. Lesca, D. Leys, C. Marescaux, D. Martin Coignard, S. Mercier, J.M. Mussini, G. Nadeau, J.P. Neau, S. Odent, E. Ollagnon, P. Parent, G. Plessis, S. Puget, G. Ruvanot, D. Saibi, C. Sainte Rose, C. Scherer-Gagou, I. Sibon, S. Sigaudy, S. Spagnolo, C. Stapf, C. Thauvin, A. Toutain, C. Verny, J. Vigneron, M. Voicu, F. Voimant, and M. Zerah.

Supplementary material

10048_2013_362_MOESM1_ESM.doc (124 kb)
ESM Table 1 DOC 124 KB
10048_2013_362_MOESM2_ESM.doc (85 kb)
ESM Table 2 DOC 86.0 KB
10048_2013_362_MOESM3_ESM.doc (53 kb)
ESM Table 3 DOC 53.5 KB


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Florence Riant
    • 1
    • 2
    • 3
    • 4
    Email author
  • Michaelle Cecillon
    • 1
  • Pascale Saugier-Veber
    • 5
    • 6
  • Elisabeth Tournier-Lasserve
    • 1
    • 2
    • 3
    • 4
  1. 1.AP-HP, GH Saint-Louis-Lariboisière-Fernand Widal, Laboratoire de Génétique MoléculaireHôpital LariboisièreParisFrance
  2. 2.INSERM U740Paris 7 UniversityParisFrance
  3. 3.Centre de référence Pour les Maladies Rares des Vaisseaux du Cerveau et de l’œil (CERVCO)GH Saint-Louis-Lariboisière-Fernand WidalParisFrance
  4. 4.Sorbonne Paris Cité, Génétique des Maladies Vasculaires, UMR-S-740, 75010Univ Paris DiderotParisFrance
  5. 5.Genetics DepartmentRouen University HospitalRouenFrance
  6. 6.INSERM U614, Institute for Biomedical ResearchUniversity of RouenRouenFrance

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