State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
State Key Laboratory of Cardiovascular Disease, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Orphanet J Rare Dis. 2021 Dec 14;16(1):513. doi: 10.1186/s13023-021-02143-2.
Thoracic aortic aneurysm and dissection (TAAD) is a hidden-onset but life-threatening disorder with high clinical variability and genetic heterogeneity. In recent years, an increasing number of genes have been identified to be related to TAAD. However, some genes remain uncertain because of limited case reports and/or functional studies. LTBP3 was such an ambiguous gene that was previously known for dental and skeletal dysplasia and then noted to be associated with TAAD. More research on individuals or families harboring variants in this gene would be helpful to obtain full knowledge of the disease and clarify its association with TAAD.
A total of 266 TAAD probands with no causative mutations in known genes had been performed wholeexome sequencing (WES) to identify potentially pathogenic variants. In this study, rare LTBP3 variants were the focus of analysis.
Two compound heterozygous mutations, c.625dup (p.Leu209fs) and c.1965del (p.Arg656fs), in LTBP3 were identified in a TAAD patient along with short stature and dental problems, which was the first TAAD case with biallelic LTBP3 null mutations in an Asian population. Additionally, several rare heterozygous LTBP3 variants were also detected in other sporadic TAAD patients.
The identification of LTBP3 mutations in TAAD patients in our study provided more clinical evidence to support its association with TAAD, which broadens the gene spectrum of LTBP3. LTBP3 should be considered to be incorporated into the routine genetic analysis of heritable aortopathy, which might help to fully understand its phenotypic spectrum and improve the diagnostic rate of TAAD.
胸主动脉瘤和夹层（TAAD）是一种隐匿性发作但危及生命的疾病，具有高度的临床变异性和遗传异质性。近年来，越来越多的基因被发现与 TAAD 相关。然而，由于病例报告和/或功能研究有限，一些基因仍然不确定。LTBP3 就是这样一个模糊的基因，它以前被认为与牙齿和骨骼发育不良有关，后来又被认为与 TAAD 有关。对携带该基因变异的个体或家庭进行更多的研究将有助于全面了解该疾病，并阐明其与 TAAD 的关联。
对 266 名无已知基因致病突变的 TAAD 先证者进行了全外显子组测序（WES），以鉴定潜在的致病性变异。在本研究中，稀有 LTBP3 变异是分析的重点。
在一名 TAAD 患者中发现了 LTBP3 中的两个复合杂合突变，c.625dup（p.Leu209fs）和 c.1965del（p.Arg656fs），伴有身材矮小和牙齿问题，这是亚洲人群中首例 LTBP3 双等位基因缺失突变的 TAAD 病例。此外，在其他散发性 TAAD 患者中也检测到了几种罕见的杂合 LTBP3 变异。
本研究中 TAAD 患者 LTBP3 突变的鉴定为其与 TAAD 的相关性提供了更多的临床证据，拓宽了 LTBP3 的基因谱。LTBP3 应被视为遗传性主动脉病常规遗传分析的一部分，这可能有助于全面了解其表型谱，并提高 TAAD 的诊断率。
