Unidad de Gestión Clínica del Corazón, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga (UMA), CIBERCV Enfermedades Cardiovasculares, Málaga, Spain.
Unidad de Insuficiencia Cardiaca Avanzada y Trasplante Cardiaco. Servicio de Cardiología. CIBERCV. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS. Universidade da Coruña (UDC). As Xubias, 15006, A Coruña, Spain.
Orphanet J Rare Dis. 2018 Jan 22;13(1):16. doi: 10.1186/s13023-017-0754-6.
Marfan syndrome (MFS) is a disorder of autosomal dominant inheritance, in which aortic root dilation is the main cause of morbidity and mortality. Fibrillin-1 (FBN-1) gene mutations are found in more than 90% of MFS cases. The aim of our study was to summarise variants in FBN-1 and establish the genotype-phenotype correlation, with particular interest in the onset of aortic events, in a broad population of patients with an initial clinical suspicion of MFS.
This single centre prospective cohort study included all patients presenting variants in the FBN-1 gene who visited a Hereditary Aortopathy clinic between September 2010 and October 2016.
The study included 90 patients with FBN-1 variants corresponding to 58 non-interrelated families. Of the 57 FBN-1 variants found, 25 (43.9%) had previously been described, 23 of which had been identified as associated with MFS, while the the remainder are described for the first time. For 84 patients (93.3%), it was possible to give a definite diagnosis of Marfan syndrome in accordance with Ghent criteria. 44 of them had missense mutations, 6 of whom had suffered an aortic event (with either prophylactic surgery for aneurysm or dissection), whereas 20 of the 35 patients with truncating mutations had suffered an event (13.6% vs. 57.1%, p < 0.001). These events tended to occur at earlier ages in patients with truncating compared to those with missense mutations, although not significantly (41.33 ± 3.77 vs. 37.5 ± 9.62 years, p = 0.162).
Patients with MFS and truncating variants in FBN-1 presented a higher proportion of aortic events, compared to a more benign course in patients with missense mutations. Genetic findings could, therefore, have importance not only in the diagnosis, but also in risk stratification and clinical management of patients with suspected MFS.
马凡综合征（MFS）是一种常染色体显性遗传疾病，其主动脉根部扩张是发病率和死亡率的主要原因。超过 90%的 MFS 病例存在原纤维蛋白 1（FBN-1）基因突变。我们的研究旨在总结 FBN-1 中的变异，并建立基因型-表型相关性，特别关注主动脉事件的发病，在一个具有初始临床疑似 MFS 的广泛患者群体中。
这项单中心前瞻性队列研究包括 2010 年 9 月至 2016 年 10 月间在遗传性主动脉病诊所就诊并发现 FBN-1 基因突变的所有患者。
该研究纳入了 90 名携带 FBN-1 变异的患者，涉及 58 个非相关家族。在所发现的 57 个 FBN-1 变异中，有 25 个（43.9%）之前已有描述，其中 23 个与 MFS 相关，其余为首次描述。根据 Ghent 标准，对 84 名患者（93.3%）可以做出明确的马凡综合征诊断。其中 44 名患者存在错义突变，其中 6 名患者发生了主动脉事件（动脉瘤或夹层的预防性手术），而 35 名截断突变患者中有 20 名发生了事件（13.6%比 57.1%，p<0.001）。尽管没有显著差异，但与错义突变患者相比，截断突变患者的事件发生年龄更早（41.33±3.77 岁比 37.5±9.62 岁，p=0.162）。
与携带错义突变的 MFS 患者相比，携带 FBN-1 截断变异的 MFS 患者发生主动脉事件的比例更高，提示具有截断变异的患者疾病更具侵袭性。因此，遗传发现不仅对诊断具有重要意义，而且对疑似 MFS 患者的风险分层和临床管理也具有重要意义。
