Abstract
ObjectiveGenetic 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Aneurysmal subarachnoid hemorrhage affects approximately 500,000 individuals per year worldwide and, despite immense medical attempts, is associated with high mortality [1]
This cohort consists of individuals with a family history of unruptured intracranial aneurysms (UIA) and/or aneurysmal subarachnoid hemorrhage (aSAH) and substantially affected patients with UIA and/or aSAH
In total we found 20, exclusively heterozygous missense variants with minor allele frequency (MAF) ≤ 0.05 (5%) in 6 genes (Table 2): 9 PCNT variants were identified in 9 patients, 4 RNF213 variants in 3 patients, 3 THSD1 variants in 6 patients, 2 ANGPTL6 variants in 3 patients, and 1 variant in ADAMTS15 and TMEM132B in 1 patient each
Summary
Aneurysmal subarachnoid hemorrhage (aSAH) affects approximately 500,000 individuals per year worldwide and, despite immense medical attempts, is associated with high mortality [1]. Large genome or exome wide association studies (GWAS or EWAS) identified several risk loci, valid disease genes have not been established [3]. Recent studies applied ES in families affected with IA/SAH and identified alterations in ANGPTL6 (angiopoietin-like 6), RNF213 (ring finger protein 213), THSD1 (thrombospondin type 1 domain containing protein 1), ARHGEF17 (Rho guanine nucleotide exchange factor 17) and PCNT (pericentrin) as genetic risk factors for this disease [4,5,6,7,8]. Other family-based ES studies reported on various candidate disease variants and genes including ADAMTS15, LOXL2 and TMEM132B,
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