Background— Genetic factors have an important role in the pathogenesis of intracranial aneurysm (IA). The results of previous studies have suggested several loci. Methods and Results— From 29 IA families with ≥3 individuals affected by IA, we used nonparametric (model-free) methods for linkage analyses, using GENEHUNTER and Merlin software. Genome-wide linkage analyses revealed 3 regions on chromosomes 17cen (maximum nonparametric logarithm of the odds score [MNS] = 3.00, nominal P =0.001), 19q13 (MNS=2.15, nominal P =0.020), and Xp22 (MNS=2.16, nominal P =0.019). We tested 4 candidate genes in these regions: the microfibril-associated protein 4 gene ( MFAP4 ) and the promoter polymorphism of the inducible nitric oxide synthase gene ( NOS2A ) on chromosome 17cen, the epsilon genotypes of the apolipoprotein E gene ( APOE ) on chromosome 19q13, and the angiotensin I converting enzyme 2 gene ( ACE2 ) on chromosome Xp22. Associations of their polymorphisms with IA were evaluated by a case-control study (100 cases: 29 probands from IA families and 71 unrelated subjects with IAs, 100 unrelated control subjects [unaffected members with IAs and absence of family history of IAs]). However, the case-control study showed that none of the polymorphisms of the examined genes had associations with IA. Conclusions— A genome-wide scan in 29 Japanese families with a high degree of familial clustering revealed 1 suggestive linkage region on chromosome 17cen and 2 potentially interesting regions on chromosomes 19q13 and Xp22. These regions were consistent with previous findings in various populations.

Background and Purpose-We sought to test the linkage of familial intracranial aneurysms (FIAs) to the ELN (elastin) locus in chromosome 7q11 reported previously. Methods-Intracranial aneurysm (IA) probands were searched from patient records or neurosurgeons' recalls in collaborating hospitals. Members of the participating probands' families who had unknown affection status were screened by MR angiography and diagnosed by digital subtraction angiography. Inclusion criteria of families for genetic analyses were as follows: at least 3 alive affected members or 2 alive affected members with at least 1 unaffected member (Ն60 years). Linkage to the ELN locus was tested with the use of GENEHUNTER by parametric and nonparametric methods. To exclude false-negatives in the linkage analysis, the lowest 5% limits of logarithms of the odds (LOD) and nonparametric LOD (NPL) scores for individual families and for the total set of families were simulated on assumption that the ELN locus is linked to FIAs. Results-Questionnaires were sent to 885 patients, and 563 responded. Seventy-nine probands were positive for family history. One hundred thirty-four family members of unknown affection status were screened. A total of 14 families with 64 members met the criteria. Linkage to the ELN locus was discarded in 11 families and was inconclusive for 3 families. The total LOD and total NPL scores for 14 families were Ϫ8.04 and Ϫ0.643, respectively. Our conclusion did not change even when the values of penetrance were changed or only affected members were analyzed. Conclusions-The majority of aggregated IA Japanese families may not have a genetic linkage to chromosome 7q11.(Stroke. 2003;34:892-900.)

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic renal disorder (incidence, 1:1,000). The mutation of PKD1 is thought to account for 85% of ADPKD. Although a considerable number of studies on PKD1 mutation have been published recently, most of them concern Caucasian ADPKD patients. In the present study, we examined PKD1 mutations in Japanese ADPKD patients. Long-range polymerase chain reaction (LR-PCR) with PKD1-specific primers followed by nested PCR was used to analyze the duplicated region of PKD1. Six novel chain-terminating mutations were detected: three nonsense mutations (Q2014X transition in exon 15, Q2969X in exon 24, and E2810X in exon 23), two deletions (2132del29 in exon10 and 7024delAC in exon 15), and one splicing mutation (IVS21-2delAG). There was also one nonconservative missense mutation (T2083I). Two other potentially pathogenic missense mutations (G2814R and L2816P) were on the downstream site of one nonsense mutation. These three mutations and a following polymorphism (8662C>T) were probably the result of gene conversion from one of the homologous genes to PKD1. Six other polymorphisms were found. Most PKD1 mutations in Japanese ADPKD patients were novel and definitely pathogenic. One pedigree did not link to either PKD1 or PKD2.

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