Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany.
Vascular Biomaterialbank Heidelberg (VBBH), Heidelberg University Hospital, Heidelberg, Germany.
Langenbecks Arch Surg. 2024 Oct 9;409(1):304. doi: 10.1007/s00423-024-03488-5.
The aim of this study was to identify causal genetic variants in patients with multiple arterial aneurysms.
From a total cohort of 3107 patients diagnosed with an arterial aneurysm from 2006 to 2016, patients with known hereditary connective tissue diseases, vasculitis, or other arterial pathologies (n = 918) were excluded. Of the remaining cohort (n = 2189), patients with at least 4 aneurysms at different arterial locations (n = 143) were included. Nine blood samples of respective patients were available and derived from the institutional vascular biomaterial bank, and analyzed by whole exome sequencing (WES). Possible candidate variants were selected based on in silico predictions: (I) Truncating variants or (II) Variants that were classified as likely pathogenic (SIFT score < 0.05 or PolyPhen score > 0.9) and with low (< 0.001) or unknown gnomAD allele frequency. The human genome databases GeneCards and MalaCards were used to correlate the variants with regard to possible associations with vascular diseases.
A total of 24 variants in 23 different genes associated with vascular diseases were detected in the cohort. One patient with eight aneurysms was heterozygous for a variant in SMAD3, for which pathogenic variants are phenotypically associated with Loeys-Dietz syndrome 3. A heterozygous variant in TNXB was found in a patient with five aneurysms. Homozygous or compound heterozygous pathogenic variants in this gene are associated with Ehlers-Danlos syndrome (classical-like). Another patient with six aneurysms carried two heterozygous TET2 variants together with a heterozygous PPM1D variant. Pathogenic variants in these genes are associated with clonal hematopoiesis of indeterminate potential (CHIP), a known risk factor for cardiovascular disease.
All nine patients in this study carried variants in genes associated with vascular diseases. Current knowledge of the specific variants is insufficient to classify them as pathogenic at the present time, underlining the need for a better understanding of the consequences of genetic variants. WES should be considered for patients with multiple arterial aneurysms to detect germline variants and to improve clinical management for the individual and family members.
本研究旨在鉴定多发性动脉动脉瘤患者中的因果遗传变异。
从 2006 年至 2016 年间诊断出患有动脉动脉瘤的 3107 例患者中，排除了已知遗传性结缔组织疾病、血管炎或其他动脉病变的患者（n=918）。在剩余的队列（n=2189）中，纳入至少有 4 个位于不同动脉部位的动脉瘤的患者（n=143）。从机构血管生物材料库中获得了相应患者的 9 份血样，并通过全外显子组测序（WES）进行分析。根据体外预测，选择可能的候选变异：（I）截断变异或（II）被归类为可能致病性的变异（SIFT 评分<0.05 或 PolyPhen 评分>0.9），且低频（<0.001）或未知 gnomAD 等位基因频率。使用人类基因组数据库 GeneCards 和 MalaCards 将变异与血管疾病的可能关联相关联。
在该队列中，共检测到 23 个与血管疾病相关的基因中的 24 个变异。一名有 8 个动脉瘤的患者在 SMAD3 中为杂合子，该变异与 Loeys-Dietz 综合征 3 表型相关。在有 5 个动脉瘤的患者中发现了 TNXB 的杂合变异。该基因的纯合或复合杂合致病性变异与埃勒斯-当洛斯综合征（经典型）相关。另一名有 6 个动脉瘤的患者携带两个 TET2 变异的杂合子，以及一个 PPM1D 变异的杂合子。这些基因中的致病性变异与克隆性造血不定潜能（CHIP）相关，这是心血管疾病的已知危险因素。
本研究中的所有 9 名患者均携带与血管疾病相关基因的变异。目前对特定变异的了解还不足以将其归类为目前的致病性，这突显了更好地了解遗传变异后果的必要性。对于多发性动脉动脉瘤患者，应考虑进行 WES，以检测种系变异，并提高个体和家庭成员的临床管理水平。
