Hôpital Bichat, Département de Génétique, Assistance Publique-Hôpitaux de Paris, Paris, France.
LVTS, INSERM U1148, Hôpital Bichat, Université Paris Diderot, Paris, France.
Genet Med. 2019 Sep;21(9):2015-2024. doi: 10.1038/s41436-019-0444-y. Epub 2019 Feb 11.
Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD.
Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed.
Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant.
This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.
遗传性胸主动脉瘤和夹层(hTAAD)是已知综合征疾病或未被充分诊断的遗传性非综合征形式(nshTAAD)的危及生命的并发症。这两种疾病均为常染色体显性遗传,具有遗传异质性。我们的目的是描述这些患者中分子诊断的相关性以及每个基因在 nshTAAD 中的作用。
纳入 226 例连续的 nshTAAD 先证者,包括年轻(<45 岁)散发性或家族性病例。进行了包含 23 个已知致病基因的下一代测序捕获面板检测。
18%的 nshTAAD 先证者中发现了 4 类或 5 类变异,10%的先证者中发现了 3 类变异。家族性病例的检出率高于散发性病例。SMAD3 和 FBN1 基因是主要的致病基因。令人意外的是,FBN1 基因中未发现提前终止密码子变异。此外,我们首次报道,携带 4 类或 5 类致病性变异的先证者主动脉夹层或手术发生的频率更高且更早。
本研究表明,使用 NGS 的遗传筛查在年轻和家族性 nshTAAD 中是有效的。致病性变异的存在具有可能的预测价值,需要进一步研究,因为它可能影响治疗。