Aneurysm, Intracranial Berry, 5

Description

Rupture of an intracranial aneurysm, an outpouching or sac-like widening of a cerebral artery, leads to a subarachnoid hemorrhage, a sudden-onset disease that can lead to severe disability and death. Several risk factors such as smoking, hypertension, and excessive alcohol intake are associated with subarachnoid hemorrhage (summary by Krischek and Inoue, 2006).

For a discussion of genetic heterogeneity of intracranial berry aneurysm, see ANIB1 (105800).

Clinical Features

Roos et al. (2004) reported a large consanguineous Dutch family in which 7 of 20 sibs had an intracranial aneurysm. Three had a subarachnoid hemorrhage (SAH) at ages 37, 42, and 45 years, respectively; 1 died with suspected SAH at age 36 years, and 3 were found to have asymptomatic cerebral aneurysms on imaging studies. Ruigrok et al. (2008) reported follow-up of the family reported by Roos et al. (2004). Two additional sibs had developed aneurysms since the original report, and 1 previously thought to be affected based on brain imaging was found not to be affected.

Mapping

Although genomewide linkage analysis of a large Dutch family with intracranial aneurysm by Roos et al. (2004) found linkage to a region on chromosome 2p13, this was later found to be erroneous. Repeat linkage analysis of this large Dutch family by Ruigrok et al. (2008) found linkage to a 7.73-cM interval on chromosome Xp22.32-p22.2 between markers DXS6807 and DXS1224 (maximum nonparametric lod score of 4.54 at marker DXS7108, p = 2.8 x 10(-6)). Six of 7 patients shared a 5-marker haplotype ranging from DXS6807 to DXS1224 inherited from the mother. However, 1 patient with an unruptured intracranial aneurysm did not inherit the risk haplotype from the mother, whereas an unaffected individual did inherit the haplotype. Inheritance of the Xp locus was consistent with X-linked dominant inheritance. Linkage analysis of this family also showed linkage to the ANIB3 locus (609122) on chromosome 1p36 under a model of autosomal recessive inheritance. Ruigrok et al. (2008) noted that aneurysms in this family may have a multigenic origin.

Yamada et al. (2004) had previously found linkage to chromosome Xp22 (maximum nonparametric lod score of 2.16) in a genomewide linkage screen of 29 Japanese families with intracranial aneurysm.