Poninska J K, Bilinska Z T, Franaszczyk M, Michalak E, Rydzanicz M, Szpakowski E, Pollak A, Milanowska B, Truszkowska G, Chmielewski P, Sioma A, Janaszek-Sitkowska H, Klisiewicz A, Michalowska I, Makowiecka-Ciesla M, Kolsut P, Stawinski P, Foss-Nieradko B, Szperl M, Grzybowski J, Hoffman P, Januszewicz A, Kusmierczyk M, Ploski R
Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland.
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
J Transl Med. 2016 May 4;14(1):115. doi: 10.1186/s12967-016-0870-4.
Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD.
51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery.
In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group).
This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.
胸主动脉瘤和夹层（TAAD）是一种隐匿但可能致命的疾病，高达40%的病例具有遗传性。遗传背景具有异质性。最近，下一代测序技术使得对基因面板进行高效且经济高效的检测成为可能。本研究的目的是确定51例TAAD患者中NGS的诊断率，并在TAAD患者家族中寻找基因型与表型的相关性。
对51例无关的TAAD患者进行全外显子组测序或TruSight One测序面板检测。我们分析了10个已确定的与胸主动脉瘤相关基因中的罕见变异。只要有可能，我们就在家族中寻找共分离情况。构建Kaplan-Meier生存曲线以比较根据基因型的无事件生存期。主动脉事件定义为急性主动脉夹层或首次计划性主动脉手术。
在21例TAAD患者中，我们发现了22个罕见变异，其中6个（27.3%）此前已有报道，16个（73.7%）是新发现的。基于分离数据、功能分析和软件评估，我们认为3个新变异是致病的，9个可能是致病的。其余4个被分类为意义不明（2个）和可能良性（2个）。总体而言，在仅考虑分类为致病的变异时，51例先证者中有9例（17.6%）检测结果为阳性；如果也包括可能致病的变异，则有18例（35.3%）。基因型阳性的先证者（n = 18）的平均无事件生存期（41岁，CI 35 - 46）比参照组，即未发现任何可能变异的患者（n = 29）（51岁，CI 45 - 57，p = 0.0083）短。当“基因型阳性”组仅限于具有“可能致病”变异的先证者时，也发现了这种效应（p = 0.0092），这进一步支持了这些变异的致病性。在TGF-β信号通路有缺陷的先证者中，平均无事件生存期特别短（37岁，CI 27 - 47）（与参照组相比，p = 0.0033）。
本研究拓宽了胸主动脉瘤和夹层的遗传背景谱，并支持其作为该疾病患者预后因素的潜在作用。
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