Postzygotic mosaicism in cerebral cavernous malformation

Abstract

BackgroundCerebral cavernous malformations (CCMs) can cause severe neurological morbidity but our understanding of the mechanisms that drive CCM formation and growth is still incomplete. Recent experimental data suggest that dysfunctional CCM3-deficient endothelial cell clones form cavernous lesions in conjunction with normal endothelial cells.ObjectiveIn this study, we addressed the question whether endothelial cell mosaicism can be found in human cavernous tissue ofCCM1germline mutation carriers.Methods and resultsBringing together single-molecule molecular inversion probes in an ultra-sensitive sequencing approach with immunostaining to visualise the lack of CCM1 protein at single cell resolution, we identified a novel late postzygoticCCM1loss-of-function variant in the cavernous tissue of a de novoCCM1germline mutation carrier. The extended unilateral CCM had been located in the right central sulcus causing progressive proximal paresis of the left arm at the age of 15 years. Immunohistochemical analyses revealed that individual caverns are lined by both heterozygous (CCM1+/−) and compound heterozygous (CCM1−/−) endothelial cells.ConclusionWe here demonstrate endothelial cell mosaicism within single caverns of human CCM tissue. In line with recent in vitro data on CCM1-deficient endothelial cells, our results provide further evidence for clonal evolution in human CCM1 pathogenesis.