Sauvigny, Thomas and Alawi, Malik and Krause, Linda and Renner, Sina and Spohn, Michael and Busch, Alice and Kolbe, Verena and Altmueller, Janine and Loescher, Britt-Sabina and Franke, Andre and Brockmann, Christian and Lieb, Wolfgang and Westphal, Manfred and Schmidt, Nils Ole and Regelsberger, Jan and Rosenberger, Georg (2020) Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage. JOURNAL OF NEUROLOGY, 267 (9). pp. 2533-2545. ISSN 0340-5354, 1432-1459
Full text not available from this repository. (Request a copy)Abstract
Objective Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH. Methods We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) <= 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives. Results We identified 20 variants with MAF <= 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified. Conclusions Our data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DEVELOPMENTAL ENDOTHELIAL LOCUS-1; POPULATION; VARIANTS; RARE; ASSOCIATION; PREVALENCE; GENETICS; PROTEIN; GROWTH; MUTATION; Subarachnoid hemorrhage; Intracranial aneurysms; Disease gene identification; Exome sequencing; EDIL3 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurochirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2021 10:45 |
| Last Modified: | 24 Mar 2021 10:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44607 |
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