Detection of somatic mutations in cerebral cavernous malformation patients using non-invasive cell-free DNA screening

Familial Cerebral Cavernous Malformations (CCM) is an inherited disease caused by mutations in three genes (KRIT1/CCM1, CCM2, or PDCD10/CCM3). Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which may lead to death or long-term neurological deficits. Clinical symptoms may differ including variable number or size of CCM lesions (ranging from a few to hundreds), even in family members who inherit the same gene mutation. This suggests a role for other factors that influence disease severity, such as genetic modifiers or somatic factors (i.e. tissue-specific DNA mutations) which may affect how the genes are regulated throughout development or disease progression. We lack medical therapies and biomarkers to know which CCM patients are at highest risk for having a hemorrhage or for developing more severe or bigger lesions. Hence, the identification of strong, non-invasive blood-based biomarkers for CCM disease severity would be useful to risk stratify patients at highest risk of hemorrhage and improve clinical management. 

Recent technological advances have provided promise for the non-invasive detection of somatic mutations in circulating cell-free DNA found in patient blood samples. Using this approach, we are investigating whether somatic mutations in CCM lesions are detectable in circulating cell-free DNA in the blood of CCM patients. The ability to non-invasively detect somatic mutations would be a better approach to investigate CCMs (especially in children) and ultimately identify a therapy that is tailored to the genetic defect.