Molecular Genetic Screening of CCM Patients: An Overview

Cerebral Cavernous Malformations (CCMs) are vascular lesions which can occur as a sporadic (80% of the cases) or a familial autosomal dominant disease (20%), the latter being characterized by the presence of multiple lesions. Three CCM genes have been identified in the last 10 years. More than 95% of familial cases and 60% of sporadic cases with multiple lesions harbor a germline heterozygous loss of function mutation in one of these 3 genes. Most mutations lead to a premature stop codon whatever the mechanism, including nonsense mutations, deletions, insertions and intronic mutations leading to abnormal splicing and frameshift. A combination of analyses, including sequencing and copy number analysis of germline DNA extracted from blood and cDNA analysis, are therefore required to ensure the best diagnostic sensitivity. Additional causative rare structural CCM gene anomalies have been identified in a research context, as well as rare causative missense mutations. These mutations are rarely searched for in a diagnostic context and explain part of the negative cases, in addition to germline mosaicism which occurs in some sporadic cases with multiple lesions. On top of germline mutations, somatic mutations occur on the wild-type allele in endothelial cells lining CCM lesions. These data established both the role of a double hit in the pathophysiology of CCM lesions and the heterogeneity of endothelial cells lining these lesions.