Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are 
identified in the vast majority of familial cases with multiple cerebral 
cavernous malformations (CCMs). However, genomic DNA sequencing combined to 
large rearrangement screening fails to detect a mutation in 5% of those cases. 
We report a family in which CCM lesions were discovered fortuitously because of 
the investigation of a developmental delay in a boy. Three members of the family 
on three generations had typical multiple CCM lesions and no clinical signs 
related to CCM. No mutation was detected using genomic DNA sequencing and 
quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA 
sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, 
resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that 
activates a cryptic splice site. This pseudoexon leads to a premature stop 
codon. These data highly suggest that deep intronic mutations explain part of 
the incomplete mutation detection rate in CCM patients and underline the 
importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. 
This kind of mutation may be responsible for apparent sporadic presentations due 
to a reduced penetrance.