Université de Paris, Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat-Claude-Bernard, Paris, France.
Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.
Genet Med. 2021 May;23(5):865-871. doi: 10.1038/s41436-020-01078-6. Epub 2021 Jan 25.
Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands.
Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene.
These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations.
This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
携带 FBN1 基因致病性嵌合变异的个体主要在家族筛查中被描述。在文献中，几乎所有这些嵌合个体都是无症状的。在本研究中，我们报告了我们团队在 5000 多名马凡综合征（MFS）先证者中的经验。
下一代测序（NGS）捕获技术使我们能够鉴定出 5 例携带 FBN1 基因致病性嵌合变异的 MFS 先证者。
这 5 例散发性嵌合先证者表现出通常见于马凡综合征的典型特征。结合文献结果，这些罕见的发现涉及单核苷酸变异和拷贝数变异。
在 MFS 患者的分子诊断中不应忽视这种被低估的发现，并需要对生物信息学分析中使用的参数进行调整。目前这 5 例有症状的 MFS 先证者携带嵌合 FBN1 致病性变异，这一事实再次强调，显然无症状的嵌合父母应进行全面的临床检查和定期的心血管随访。我们建议，对于那些未发现单个核苷酸致病性变异或外显子缺失/重复的具有典型 MFS 的个体，应通过 NGS 捕获面板进行检测，并采用适应性变异呼叫分析。
