Cerebral Cavernous Malformations (CCM) can occur sporadically or are caused by mutations in one of three identified genes. CCM often remain clinically silent until a mutation carrier suffers a stroke or seizure. Pre-symptomatic genetic testing has been valuable to follow and manage CCM mutation carriers. During routine diagnostic testing we identified a 2-base pair change in seven unrelated people of Ashkenazi Jewish (AJ) heritage. Due to 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.
Transcripts arising from the normal and mutant alleles were examined by RT-PCR from affected and unaffected AJ CCM family members. A synthetic splicing system using a chimeric exon was employed to visualize the effects of the change on splice donor site utilization.
The 2-base pair change in CCM2, c.30+5_6delinsTT, segregated with affected status in the study families. RT-PCR revealed loss of the transcript allele that was in phase with the mutation. The 2-base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Re-sequencing of the genomic region proximal and distal to the CCM2 gene mutation reveal a common SNP haplotype in affected individuals.
The 2-base pair change in CCM2, c.30+5_6delinsTT, disrupts proper splice donor utilization leading to a degraded transcript. SNP haplotype analysis demonstrates that this mutation is due to a founder in the AJ population. These data have the potential to simplify genetic testing for CCM in the AJ population.