Page 16 - Read Online

Page 2 of 14 Ricci et al. Vessel Plus 2021;5:31 https://dx.doi.org/10.20517/2574-1209.2021.28

a familial autosomal dominant disorder (FCCM) (20% of cases), with incomplete clinical and
[1]
neuroradiological penetrance and great inter-individual variability .
[2,3]
Sporadic forms usually present with a single lesion on MRI , although multiple lesions have been reported
[4,5]
in some cases . In contrast, familial forms typically exhibit multiple lesions, which increase in number and
size over time . CCM result in a variety of clinical manifestations, including recurrent headaches, seizures,
[6]
focal neurological deficit, and hemorrhage, with onset usually during adult life, but symptoms can also start
in early infancy or in old age .
[1]

In addition to neural lesions, extraneural cavernous malformations have been described in the familial form,
in particular cutaneous and retinal vascular malformations .
[7,8]

Three CCM genes have been identified so far: CCM1/KRIT1 , CCM2/MGC4607 , and CCM3/PDCD10 .
[11]
[10]
[9]
Almost 80% of CCM patients affected with a genetic form of the disease carry a heterozygous germline
mutation in one of these genes .
[1]
The purpose of this review is to provide an update on recent advances in molecular genetics of cerebral
cavernous malformations. We provide the main features of the three genes and an updated listing of CCM
pathogenic variants published so far in the peer-reviewed literature. We summarize the available data on
penetrance, phenotype-genotype correlations, and founder effect for the variants described in the three
CCM genes. Moreover, we briefly examine the different mutation screening methods in the genetic
diagnostic approach to CCM and discuss the main aspects of genetic counseling.

CCM GENES
Mutations in the KRIT1 gene have been found in 53%-65% of the familial forms of CCM. Mutations in the
CCM2 gene account for approximately 20% of the familial CCM cases, whereas 10%-16% of CCM families
[12]
harbor mutations in the PDCD10 gene .The existence of a potential fourth gene linked to CCM has long
been postulated, since 5%-15% of familial cases cannot be explained by mutations in the three known CCM
[11]
genes. It is however rather unlikely now, more than 15 years after the identification of the PDCD10 gene .
It is probable that the very few CCM families apparently negative for mutations in KRIT1, CCM2, and
PDCD10 genes harbor a pathogenic variant not identified by the routinely used techniques (e.g., a variant
outside the screened exonic regions or a copy number neutral genomic rearrangement in one of the three
genes ).
[13]

Thus far, more than 350 different KRIT1/CCM2/PDCD10 germline mutations have been identified and
[14]
included in the Human Gene Mutation Database (HGMD) . These variants are highly stereotyped. Almost
all of them introduce a premature termination codon in the protein, through various mechanisms, such as
nonsense, splice-site, and frameshift mutations, as well as larger genomic rearrangements. Of note, even
though the consequences are highly stereotyped, germline CCM mutations are usually present in only one
or few families and are rarely recurrent .
[1]

The molecular mechanisms responsible for the formation of CCM lesions in the presence of CCM gene
mutations remain unclear. The proteins encoded by these genes are essential for regulating the angiogenesis
during embryonic development and vascular postnatal stages of development [9,15-17] . They are involved in the
maintenance of junctional integrity between adjacent vascular endothelial cells [18,19] and are expressed in
endothelium, neurons, and astrocytes [20,21] . Endothelial cells seem to be the cell of origin for CCM [22,23] .