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.

  • Brief Communication
  • Published:

Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations

European Journal of Human Genetics (2024)Cite this article

Subjects

Abstract

Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing. However, a loss of heterozygosity in CCM2 was observed on cDNA sequences in one of the two affected members, which strongly suggested that this locus might be involved. Whole genome sequencing (WGS) identified a balanced structural variant on chromosome 7 with a breakpoint interrupting the CCM2 gene, preventing normal mRNA synthesis. These data underline the importance of WGS in undiagnosed patients with typical multiple CCM.

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: Description of the patients and sequencing.
Fig. 2: Characterization of the structural variant.

Similar content being viewed by others

Data availability

The datasets generated during the current study are available from the corresponding author.

References

  1. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol. 2007;6:237–44.

    Article  CAS  PubMed  Google Scholar 

  2. Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E. Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J. 2010;277:1070–5.

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Spiegler S, Najm J, Liu J, Gkalympoudis S, Schröder W, Borck G, et al. High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. Mol Genet Genom Med. 2014;2:176–85.

    Article  Google Scholar 

  5. Riant F, Cecillon M, Saugier-Veber P, Tournier-Lasserve E. CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions. Neurogenetics. 2013;14:133–41.

    Article  CAS  PubMed  Google Scholar 

  6. 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  PubMed  Google Scholar 

  7. Pilz RA, Schwefel K, Weise A, Liehr T, Demmer P, Spuler A, et al. First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations. Sci Rep. 2020;10:6306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang ZD, Du J, Lam H, Abyzov A, Urban AE, Snyder M, et al. Identification of genomic indels and structural variations using split reads. BMC Genomics. 2011;12:375.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the family for participating in this study. This research was made possible through access to the data generated by the France Genomic Medicine Plan 2025.

Funding

No financial assistance was received in support of the study.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Hôpital de l’Archet 2, CHU de Nice, Nice, France

    Annabelle Chaussenot

  2. Department of Neurology, Gui de Chauliac Montpellier University Hospital, Montpellier University, Montpellier, France

    Xavier Ayrignac & Pierre Labauge

  3. Department of Medical Genetics, Hospices Civils de Lyon, Groupe Hospitalier Est, Bron, France

    Nicolas Chatron

  4. Laboratoire AURAGEN (Plan France Médecine Génomique 2025), Lyon, France

    Nicolas Chatron & Florence Riant

  5. Department of Neurovascular Molecular Genetics AP-HP, Saint-Louis Hospital, Paris, France

    Terry Granchon-Riolzir, Elisabeth Tournier-Lasserve & Florence Riant

  6. Reference Center for Rare Vascular Diseases of the Central Nervous System and the Retina (CERVCO), APHP Lariboisiere Hospital, Paris, France

    Terry Granchon-Riolzir, Elisabeth Tournier-Lasserve & Florence Riant

Authors
  1. Annabelle Chaussenot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xavier Ayrignac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Chatron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terry Granchon-Riolzir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Labauge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabeth Tournier-Lasserve
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florence Riant
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FR designed the work that led to the submission, acquired data, and played an important role in interpreting the results. AC, PL, and XA acquired data and revised the manuscript. TG acquired the data. NC played an important role in interpreting the results and revised the manuscript. ETL revised the manuscript.

Corresponding author

Correspondence to Florence Riant.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

Study participants or legal representatives gave written informed consent for clinical testing, research use and publication. The analyses were performed in accordance with French regulations and the principles of the Declaration of Helsinki.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chaussenot, A., Ayrignac, X., Chatron, N. et al. Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01626-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41431-024-01626-7

Search

Advanced search

Quick links