Genome-wide linkage analysis combined with genome sequencing in large families with intracranial aneurysms

被引：6

作者：

Bakker, Mark K. ^{[1
]}

Cobyte, Suze ^{[1
]}

Hennekam, Frederic A. M. ^{[2
]}

Rinkel, Gabriel J. E. ^{[1
]}

Veldink, Jan H. ^{[1
]}

Ruigrok, Ynte M. ^{[1
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr, Utrecht, Netherlands

[2] Utrecht Univ Med Ctr, Dept Genet, Utrecht, Netherlands

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2022年 / 30卷 / 07期

基金：

欧洲研究理事会;

关键词：

SUBARACHNOID HEMORRHAGE; GENETICS; PREVALENCE; MUTATIONS; TESTS; RISK; SEX; AGE;

D O I：

10.1038/s41431-022-01059-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging variants for IA in three large Dutch families with multiple affected members with IA (N = 9, 11, and 6). By combining linkage analysis and genome sequencing (GS), we identified six rare and damaging variants for which all cases within one of the families were heterozygous. These variants were p.Tyr87Cys in SYCP1, p.Phe1077Leu in FMNL2, p.Thr754Lys in TBC1D2, p.Arg321His in ZNF782, p.Arg979Trp in CCDC180, and p.Val125Met in NCBP1. None of the variants showed association with IA status in a large cohort of 937 patients from the general IA patient population and 1046 controls. Gene expression in IA and cerebral artery tissue further prioritized FMNL2 and TBC1D2 as potential important players in IA pathophysiology. Further studies are needed to characterize the functional consequences of the identified variants and their role in the biological mechanisms of IA.

引用

页码：833 / 840

页数：8

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