Division of Neurointervention Clinic, Department of Radiology, Neurointervention Clinic, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Korean J Radiol. 2022 Jan;23(1):101-111. doi: 10.3348/kjr.2021.0467. Epub 2021 Oct 1.
Familial intracranial aneurysms (FIAs) are found in approximately 6%-20% of patients with intracranial aneurysms (IAs), suggesting that genetic predisposition likely plays a role in its pathogenesis. The aim of this study was to identify possible IA-associated variants using whole exome sequencing (WES) in selected Korean families with FIA.
Among the 26 families in our institutional database with two or more IA-affected first-degree relatives, three families that were genetically enriched (multiple, early onset, or common site involvement within the families) for IA were selected for WES. Filtering strategies, including a family-based approach and knowledge-based prioritization, were applied to derive possible IA-associated variants from the families. A chromosomal microarray was performed to detect relatively large chromosomal abnormalities.
Thirteen individuals from the three families were sequenced, of whom seven had IAs. We noted three rare, potentially deleterious variants ( c.1315G>A, c.968C>T, and c.58C>T), which are the most promising candidates among the 11 potential IA-associated variants considering gene-phenotype relationships, gene function, co-segregation, and variant pathogenicity. Microarray analysis did not reveal any significant copy number variants in the families.
Using WES, we found that rare, potentially deleterious variants in , , and genes are likely responsible for the subsets of FIAs in a cohort of Korean families.
家族性颅内动脉瘤（FIAs）约占颅内动脉瘤（IAs）患者的 6%-20%，提示遗传易感性可能在其发病机制中起作用。本研究旨在通过全外显子组测序（WES）鉴定具有 FIA 的选定韩国家族中可能与 IA 相关的变异。
在我们机构数据库中，有 26 个具有两个或更多 IA 受累一级亲属的家族，选择三个在 IA 方面遗传丰富（家族内多发性、早发性或常见部位受累）的家族进行 WES。应用基于家族的方法和基于知识的优先级筛选策略，从家族中得出可能与 IA 相关的变异。进行染色体微阵列分析以检测相对较大的染色体异常。
对来自三个家族的 13 个人进行了测序，其中 7 人患有 IA。我们注意到三个罕见的、可能具有破坏性的变异（c.1315G>A、c.968C>T 和 c.58C>T），考虑到基因-表型关系、基因功能、共分离和变异致病性，这些变异是 11 个潜在与 IA 相关的变异中最有希望的候选者。微阵列分析未发现家族中有任何显著的拷贝数变异。
使用 WES，我们发现 、 和 基因中的罕见、可能具有破坏性的变异可能导致韩国家族中 FIAs 的亚群。
