摘要
目的对1例马凡综合征(MFS)患儿的原纤维蛋白基因-1(FBN1)进行基因检测与超声心动图检查,分析其分子发病机制并探讨超声心动图表型。方法收集1例MFS患儿及家系成员临床资料,经超声心动图检查后,利用二代基因测序技术对FBN1基因进行外显子测序,用Sanger测序对筛查出来的可能致病突变位点进行家系验证,通过预测软件预测突变位点致病性,结合文献对突变位点致病性与超声心动图表型进行分析。结果患儿超声心动图检查表现为以二尖瓣脱垂并重度关闭不全为显著特征的心血管异常。测序结果发现FBN1基因存在杂合突变c.6496+1G>C,为未报道过的新突变,而患儿家系正常成员均未检出该突变。该突变位于经典剪切位点上,可能影响mRNA剪切。同时Mfold、MaxEntScan和MutationTaster软件分析预测该突变为致病性突变。综合分析,该患儿可诊断为以二尖瓣脱垂为显著特征的MFS,且c.6496+1G>C(exon53)剪切突变可推测为新发致病性突变。结论本文首次报道c.6496+1G>C(exon53)剪切突变,扩展了FBN1基因突变谱,结合心血管表型与文献分析,为MFS的突变基因型与心血管表型研究提供了新的思路,并进一步为临床精准医疗提供一定的理论基础。
Objective To perform fibrillin-1 (FBN1) gene detection and echocardiography for a child with Marfan syndrome (MFS), and to investigate the molecular pathogenesis and echocardiographic phenotype of MFS. Methods The clinical data of a child with MFS and family members were collected, and after echocardiography, next-generation sequencing was used to perform exon sequencing for the FBN1 gene, and Sanger sequencing was used for the validation of possible pathogenic mutation sites in this family. A prediction software was used to predict the pathogenicity of mutation sites, and the pathogenicity of mutation sites and echocardiographic phenotype were analyzed with reference to related articles.Results The child had the echocardiographic manifestation of cardiovascular anomalies characterized by mitral valve prolapse with severe mitral insufficiency. The results of sequencing showed a novel heterozygous mutation, c.6496+1G>C, in the FBN1 gene, which was not detected in normal family members. This mutation was located on a classical splice site and might affect mRNA splicing. Mfold, MaxEntScan, and MutationTaster predicted that this novel splicing mutation was a pathogenic mutation. Therefore, the child was diagnosed with MFS manifesting as mitral valve prolapse, and the c.6496+1G>C (exon53) splicing mutation was predicted to be a novel pathogenic mutation.Conclusion The c.6496+1G>C (exon53) splicing mutation reported in this article for the first time expands the mutation spectrum of the FBN1 gene. Further exploration of the association between cardiovascular phenotypes and splicing mutation through literature review provides new ideas for the research on the genotype and cardiovascular phenotype of MFS and a theoretical basis for precision medicine in clinical practice.
作者
周言博
王月丽
ZHOU Yanbo;WANG Yueli(Department of Ultrasound, Hulin People's Hospital, Hulin 158400, China)
出处
《精准医学杂志》
2019年第2期126-130,134,共6页
Journal of Precision Medicine
基金
国家自然科学基金青年科学基金项目(81501486)
