Department of Cardiovascular Genetics and The Laboratory of Forensic Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Mol Genet Genomic Med. 2020 Sep;8(9):e1378. doi: 10.1002/mgg3.1378. Epub 2020 Jun 29.
Thoracic aortic aneurysm and dissection (TAA/D) represents a potentially lethal disease group characterized by an increased risk of dissection or rupture. Only a small percentage (approximately 30%) of individuals with nonsyndromic familial TAA/D have a pathogenic variant in one of the genes that have been found to be associated with the disease.
A targeted sequencing panel and direct sequencing approach were used to identify causative mutations in the index patients and other family members.
In this study we report two apparently unrelated Cypriot families with nonsyndromic familial TAA/D. The proband A is a female patient diagnosed with TAA/D and intracranial aneurysm and opted for an elective intervention. The proband B is a male patient who was diagnosed with TAA/D and underwent cardiac surgery. Sequencing analysis identified a novel splice site variant (c.871+1G>A) in SMAD3 which is shown to be associated with the disease. Analysis of mRNA from the patient's tissue confirmed aberrant splicing and exon 6 skipping.
Our findings expand the mutation spectrum of variants that have been shown to be associated with nonsyndromic familial TAA/D. This study demonstrates the importance of a comprehensive clinical and genetic evaluation aiming at early diagnosis and intervention.
胸主动脉瘤和夹层（TAA/D）是一组具有潜在致命性的疾病，其特征是夹层或破裂的风险增加。只有一小部分（约 30%）非综合征性家族性 TAA/D 患者在与该疾病相关的基因之一中存在致病性变异。
使用靶向测序面板和直接测序方法来鉴定索引患者和其他家庭成员中的致病突变。
在这项研究中，我们报告了两个来自塞浦路斯的非综合征性家族性 TAA/D 的显然不相关的家族。先证者 A 是一名女性患者，被诊断为 TAA/D 和颅内动脉瘤，并选择了择期干预。先证者 B 是一名男性患者，被诊断为 TAA/D，并接受了心脏手术。测序分析在 SMAD3 中发现了一个新的剪接位点变异（c.871+1G>A），该变异与该疾病相关。对患者组织的 mRNA 分析证实了异常剪接和外显子 6 跳跃。
我们的发现扩展了与非综合征性家族性 TAA/D 相关的变异的突变谱。本研究证明了进行全面临床和遗传评估以实现早期诊断和干预的重要性。
