Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27

Cerebral cavernous malformation (CCM) is a Mendelian model of stroke,characterized by focal abnormalities in small intracranial blood vesselsleading to hemorrhage and consequent strokes and/or seizures. A significantfraction of cases is inherited as an autosomal dominant trait withincomplete penetrance. Among Hispanic Americans, virtually all CCM isattributable to a founder mutation localized to 7q ( CCM1 ). Recentanalysis of non-Hispanic Caucasian kindreds, however, has excluded linkageto 7q in some, indicating at least one additional CCM locus. We now reportanalysis of linkage in 20 non-Hispanic Caucasian kindreds with familialCCM. In addition to linkage to CCM1, analysis of linkage demonstrateslinkage to two new loci, CCM2 at 7p13-15 and CCM3 at 3q25.2-27. Multilocusanalysis yields a maximum lod score of 14.11, with 40% of kindreds linkedto CCM1, 20% linked to CCM2 and 40% linked to CCM3, with highly significantevidence for linkage to three loci (linkage to three loci supported with anodds ratio of 2.6 x 10(5):1 over linkage to two loci and 1.6 x 10(9):1 overlinkage to one locus). Multipoint analysis among families with highposterior probabilities of linkage to each locus refines the locations ofCCM2 and CCM3 to approximately 22 cM intervals. Linkage to these three locican account for inheritance of CCM in all kindreds studied. Significantlocus- specific differences in penetrance are identified. These findingshave implications for genetic testing of this disorder and represent animportant step toward identification of the molecular basis of thisdisease.