Universität zu Köln

Sauvigny, Thomas, Alawi, Malik, Krause, Linda ORCID: 0000-0002-8490-5717, Renner, Sina, Spohn, Michael, Busch, Alice, Kolbe, Verena, Altmueller, Janine, Loescher, Britt-Sabina, Franke, Andre, Brockmann, Christian, Lieb, Wolfgang, Westphal, Manfred, Schmidt, Nils Ole ORCID: 0000-0001-6910-8843, Regelsberger, Jan and Rosenberger, Georg (2020). Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage. J. Neurol., 267 (9). S. 2533 - 2546. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-1459

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sauvigny, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Alawi, Malik UNSPECIFIED UNSPECIFIED UNSPECIFIED Krause, Linda UNSPECIFIED orcid.org/0000-0002-8490-5717 UNSPECIFIED Renner, Sina UNSPECIFIED UNSPECIFIED UNSPECIFIED Spohn, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Alice UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolbe, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Loescher, Britt-Sabina UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Brockmann, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Lieb, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Westphal, Manfred UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Nils Ole UNSPECIFIED orcid.org/0000-0001-6910-8843 UNSPECIFIED Regelsberger, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenberger, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-334489
DOI:	10.1007/s00415-020-09865-6
Journal or Publication Title:	J. Neurol.
Volume:	267
Number:	9
Page Range:	S. 2533 - 2546
Date:	2020
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-1459
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEVELOPMENTAL ENDOTHELIAL LOCUS-1; POPULATION; VARIANTS; RARE; ASSOCIATION; PREVALENCE; GENETICS; PROTEIN; GROWTH; MUTATION Multiple languages Clinical Neurology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33448