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Ricci et al. Vessel Plus 2021;5:31 Vessel Plus
DOI: 10.20517/2574-1209.2021.28

Review Open Access

Molecular genetic analysis of cerebral cavernous

malformations: an update

Claudia Ricci, Giulia Riolo, Stefania Battistini
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena 53100, Italy.

Correspondence to: Dr. Stefania Battistini, Department of Medical, Surgical and Neurological Sciences, University of Siena, viale
Bracci 2, Siena 53100, Italy. E-mail: stefania.battistini@unisi.it

How to cite this article: Ricci C, Riolo G, Battistini S. Molecular genetic analysis of cerebral cavernous malformations: an update.
Vessel Plus 2021;5:31. https://dx.doi.org/10.20517/2574-1209.2021.28

Received: 11 Feb 2021 First Decision: 24 Mar 2021 Revised: 30 Mar 2021 Accepted: 14 May 2020 Published: 23 Jun 2021

Academic Editor: Jun Zhang Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Cerebral cavernous malformations (CCM) can occur either as sporadic or familial form with autosomal dominant
inheritance. Three CCM genes have been identified: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). In this
review, we provide an overall update on genetics of cerebral cavernous malformations. We discuss the main
features of these three genes and provide an updated listing of the mutations identified so far. Most of them lead to
a premature stop codon regardless of the nature of the variation, including nonsense mutations, small
deletions/insertions, and intronic/exonic substitutions causing an altered splicing and a frame-shift. In addition,
deletions or duplications of one or more exons of CCM genes can be responsible for the disease. We examine the
use of different mutation screening methods to identify all these mutations, providing a comprehensive approach
to CCM genetic diagnosis. We also report the main strategies to evaluate the actual impact of the mutations on the
protein function. Moreover, we recapitulate the available data on penetrance, phenotype-genotype correlations,
and founder effect. Finally, we discuss the main aspects of genetic counseling, including genetic risk assessment in
family members, in sporadic patients with multiple CCMs, and in the case of de novo mutations.

Keywords: KRIT1, CCM2, PDCD10 gene variants, de novo mutation, penetrance, phenotype-genotype correlation,
genetic counseling, screening methods

INTRODUCTION
Cerebral cavernous malformations (CCM) are vascular lesions that can occur as a sporadic (80% of cases) or

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
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