PURPOSE: Cerebral cavernous malformations can occur sporadically or are caused 
by mutations in one of three identified genes. Cerebral cavernous malformations 
often remain clinically silent until a mutation carrier suffers a stroke or 
seizure. Presymptomatic genetic testing has been valuable to follow and manage 
cerebral cavernous malformation mutation carriers. During routine diagnostic 
testing, we identified a two base pair change in seven unrelated people of 
Ashkenazi Jewish heritage. Because of the location of the variant beyond the 
invariant splice donor sequence, the change was reported as a variant of unknown 
significance. In this study, we determined whether this change was a 
disease-causing mutation and whether it represents a founder mutation in the 
Ashkenazi Jewish population.
METHODS: Transcripts arising from the normal and mutant alleles were examined by 
reverse transcription-polymerase chain reaction from affected and unaffected 
Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic 
splicing system using a chimeric exon was used to visualize the effects of the 
change on splice donor site utilization.
RESULTS: The two base pair change in CCM2, c.30 + 5_6delinsTT, segregated with 
affected status in the study families. Reverse transcription-polymerase chain 
reaction revealed loss of the transcript allele that was in phase with the 
mutation. The two base pair change, when tested in an in vitro synthetic 
splicing system, altered splice donor site utilization. Resequencing of the 
genomic region proximal and distal to the CCM2 gene mutation revealed a common 
single-nucleotide polymorphism haplotype in affected individuals.
CONCLUSIONS: The two base pair change in CCM2, c.30 + 5_6delinsTT, disrupted 
proper splice donor utilization leading to a degraded transcript. Single 
nucleotide polymorphism haplotype analysis demonstrated that this mutation was 
due to a founder in the Ashkenazi Jewish population. These data have the 
potential to simplify genetic testing for cerebral cavernous malformation in the 
Ashkenazi Jewish population.