It has been proven that falling below the threshold of haploinsufficiency for CCMs in microvascular ECs is an essential first step for the pathogenesis of CCM lesions in vivo, generated from both zebrafish [26,28] and mice Ccms mutant models [29], while the genetic “two-hit” mechanism is just the most extreme end (null) at the spectrum of haploinsufficiency. The gene discussed is SNRPB; the disease is cerebral cavernous malformation.