A Rare Variant of ANK3 Is Associated With Intracranial Aneurysm

Junyu Liu; Xin Liao; Jilin Zhou; Bingyang Li; Lu Xu; Songlin Liu; Yifeng Li; Dun Yuan; Chongyu Hu; Weixi Jiang; Junxia Yan

doi:10.3389/fneur.2021.672570

A Rare Variant of ANK3 Is Associated With Intracranial Aneurysm

Front Neurol. 2021 Jun 25:12:672570. doi: 10.3389/fneur.2021.672570. eCollection 2021.

Authors

Junyu Liu¹, Xin Liao^{2

3}, Jilin Zhou¹, Bingyang Li², Lu Xu¹, Songlin Liu¹, Yifeng Li¹, Dun Yuan¹, Chongyu Hu⁴, Weixi Jiang¹, Junxia Yan^{2

5}

Affiliations

¹ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
² Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
³ The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁴ Department of Neurology, Hunan People's Hospital, Changsha, China.
⁵ Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha, China.

Abstract

Intracranial aneurysm (IA) is a cerebrovascular disorder in which abnormal dilation of a blood vessel results from weakening of the blood vessel wall. The aneurysm may rupture, leading to subarachnoid hemorrhage with severe outcomes. This study was conducted to identify the genetic factors involved in the etiology of IA. Whole-exome sequencing was performed in three IA-aggregate families to identify candidate variants. Further association studies of candidate variants were performed among sporadic cases and controls. Bioinformatic analysis was used to predict the functions of candidate genes and variants. Twenty variants were identified after whole-exome sequencing, among which eight were selected for replicative association studies. ANK3 c.4403G>A (p.R1468H) was significantly associated with IA (odds ratio 4.77; 95% confidence interval 1.94-11.67; p-value = 0.00019). Amino acid R1468 in ANK3 was predicted to be located in the spectrin-binding domain of ankyrin-G and may regulate the migration of vascular endothelial cells and affect cell-cell junctions. Therefore, the variation p.R1468H may cause weakening of the artery walls, thereby accelerating the formation of IA. Thus, ANK3 is a candidate gene highly related to IA.

Keywords: ANK3; candidate gene; intracranial aneurysm; neurosurgery; whole exome sequencing.