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Ricci et al. Vessel Plus 2021;5:31 https://dx.doi.org/10.20517/2574-1209.2021.28 Page 11 of 14

proband’s parents.

The real percentage of cases caused by de novo pathogenic variants is unknown, because genetic analysis in
[79]
parents is not always possible . Individuals carrying a de novo germline pathogenic variant in all three
CCM genes, most frequently in PDCD10, have been reported [10,11,53,54,56,64,65,80] . These mutations may occur
randomly at any stage of embryonic development or at the germline level in the parents’ gametes. However,
other possible explanations, including incorrect attribution of paternity or maternity (in the case of assisted
reproduction), could be considered. All these aspects should be considered for a correct genetic counseling.

CONCLUSIONS
In the last years, great progress has been obtained in understanding the genetic bases of CCM and in CCM
patients’ characterization. The advances of the molecular biology technologies, as well as a combined use of
different methods, may now unravel the genetic cause of the majority of CCM cases. Genetic data should
always be associated with a detailed clinical characterization of patients and, when possible, their affected
family members. This may allow better defining several aspects of the disease, such as the relationship
between phenotypes and genotypes and the penetrance of the variants identified in the three CCM genes. In
this respect, it is of fundamental importance for the scientific community to have access to updated
databases reporting genetic and phenotypic data derived from the literature. This approach may allow
reaching a deeper knowledge of the disease, to better understand CCM pathophysiology, guide genetic
counseling, and eventually improve clinical care of patients.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study: Battistini S, Ricci C
Performed graphical design, as well as provided technical, and material support: Riolo G

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.

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