OBJECTIVE: To study the molecular genetic and clinical features of cerebral 
cavernous malformations (CCM) in a cohort of Spanish patients.
METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct 
sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic 
cases of CCM patients of Spanish extraction. When available, RNA studies were 
performed seeking for alternative or cryptic splicing.
RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated 
proteins, were identified in 29 familial forms and in three sporadic cases. The 
repertoire includes six novel non-sense and frameshift mutations in CCM1 and 
CCM3. We also found four missense mutations, one of them located at the third 
NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 
6. We found four genomic deletions with the loss of the whole CCM2 gene in one 
patient and a partial loss of CCM1and CCM2 genes in three other patients. Four 
families had mutations in CCM3. The results include a high frequency of intronic 
variants, although most of them localize out of consensus splicing sequences. 
The main symptoms associated to clinical debut consisted of cerebral 
haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM 
with Noonan and Chiari syndromes and delayed menarche is reported.
CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations 
in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic 
patients). The results include 13 new mutations of CCM genes and the main 
clinical symptoms that deserves consideration in molecular diagnosis and genetic 
counselling of cerebral cavernous malformations.