Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage
Ist Teil von
Journal of neurology, 2020-09, Vol.267 (9), p.2533-2545
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2020
Quelle
SpringerNature Journals
Beschreibungen/Notizen
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.