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


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.

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Fig. 1: Description of the patients and sequencing.
Fig. 2: Characterization of the structural variant.

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Data availability

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


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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.


No financial assistance was received in support of the study.

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Authors and Affiliations



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.

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The authors declare no competing interests.

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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.

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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).

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