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Ricci et al. Vessel Plus 2021;5:31 https://dx.doi.org/10.20517/2574-1209.2021.28 Page 7 of 14

Comparison of the MRI features of KRIT1, CCM2, and PDCD10 mutation carriers suggested that the
increment with age of the number of lesions on MRI gradient echo sequence (GRE) varies according to the
mutated CCM gene. Fewer brain lesions on GRE MRI and a slower rate of lesion development have been
[54]
observed in CCM2 mutation carriers compared to patients with KRIT1 gene variants .

PENETRANCE
[57]
Clinical penetrance varies among the CCM genes and may be specific to the pathogenic variant . Clinical
penetrance is estimated to be 60%-88% in CCM1, 100% in CCM2, and 63% in CCM3 families [53,58,59] . Within
KRIT1 positive families, both clinical and neuroradiological penetrance are incomplete and age dependent.
Neuroradiological penetrance of CCM was previously considered to be complete or almost complete.
Nevertheless, molecular screening of asymptomatic individuals revealed that cerebral MRI penetrance is
also incomplete, even using the highly sensitive GRE sequences, and age dependent [53,60] .

Among the three CCM genes, CCM2 is the only one reported with 100% of clinical and neuroradiological
penetrance . However, in 2018, Scimone et al. found seven members of a family with a novel mutation,
[59]
[61]
c.1555-1G>A (published as IVS10-1G>A), in whom only five of them showed lesions on MRI scan.
Therefore, for the first time, a penetrance < 100%, equivalent to 70%, was reported for the CCM2 gene.

FOUNDER PATHOGENIC VARIANTS
To date, more than 350 different mutations in the three CCM genes have been reported in the HGMD.
Although most of them are family specific, four founder pathogenic variants have been identified so far that
may be useful for stratifying genetic analysis in specific populations.

A founder effect has been shown for the pathogenic variant c.1363C>T (p.Gln455Ter) in the KRIT1 gene,
referred to as “the common Hispanic variant”, identified in about 70% of affected families with ancestry
from north Mexico and the American Southwest [62,63] .

A 77.6-kb deletion spanning exons 2-10 of the CCM2 gene resulted a common founder deletion with a high
prevalence (up to 22%) in the United States population [42,64] , while it was rare in the Italian population .
[65]
In the Italian population, a founder effect in four Sardinian families was observed for the mutation
[66]
c.987C>A (p.Cys329Ter) in exon 10 of the KRIT1 gene .
More recently, a two-base pair change, c.30+5_30+6delinsTT, affecting messenger RNA splicing of the
CCM2 gene, was identified in seven apparently unrelated probands from 10 different kindreds of Ashkenazi
Jewish descent, resulting a founder mutation in the Ashkenazi Jewish population .
[67]
Finally, a redundant 14-bp deletion (c.554_567del) in exon 5 of CCM2 gene has been described in patients
from the Iberian Peninsula [68,69] . However, in this case, a haplotype study has not been performed to
determine a founder effect.

The main features of the founder pathogenic variants are summarized in Table 1.

GENETIC TESTING
The molecular testing approach for CCM includes several methods to ensure the best diagnostic accuracy.
A stepwise protocol may provide a high screening sensitivity, rationalizing costs and times of the analysis.