Zhao Xiaopei, Hou Cuilan, Xiao Tingting, Xie Lijian, Li Yun, Jia Jia, Zheng Junming, Zhang Yongwei, Xu Meng
Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China.
NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China.
Transl Pediatr. 2020 Oct;9(5):610-618. doi: 10.21037/tp-20-81.
Bicuspid aortic valve (BAV) is a common congenital heart defect (0.5-2.0% in the adult), potentially an onset factor of aortic stenosis (AS). Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of BAV, but the genetic basis underlying this cardiac malformation remains poorly understood.
Whole exome sequencing (WES) was utilized to uncover genetic variants associated with BAV. Pathogenicity score and mode of inheritance through bioinformatics tools were undertook to identify the possible disease-causing mutation.
A heterozygous Ala58Val mutation in Myosin binding protein C (Mybpc3) was identified out of 2,840 variants in an 11-year-old female patient. The proband and her father were confirmed to be heterozygous carriers of 173 C>T hybridization, and her mother was homozygous negative of the mutation as confirmed through Sanger sequencing. Expression of mRNA in the proband and her father, who also carries the mutation, were almost half of proband's mother. Indicating Mybpc3 (p.Ala58Val) mutation affected its expression, and may play crucial roles for heritable BAV.
To our knowledge, this is the first time to report Mybpc3 heterozygous variant associated with heritable BAV. The relationship between the location of Mybpc3 mutation and BAV may provide a novel perspective of understanding this disorder.
二叶式主动脉瓣（BAV）是一种常见的先天性心脏缺陷（在成年人中占0.5 - 2.0%），可能是主动脉狭窄（AS）的发病因素。越来越多的证据表明遗传风险因素在BAV的发病机制中起关键作用，但这种心脏畸形的遗传基础仍知之甚少。
利用全外显子组测序（WES）来发现与BAV相关的基因变异。通过生物信息学工具进行致病性评分和遗传模式分析，以确定可能的致病突变。
在一名11岁女性患者的2840个变异中，鉴定出肌球蛋白结合蛋白C（Mybpc3）中的一个杂合Ala58Val突变。先证者和她的父亲经证实是173 C>T杂合的携带者，通过桑格测序证实她的母亲是该突变的纯合阴性。先证者和同样携带该突变的父亲的mRNA表达量几乎是先证者母亲的一半。表明Mybpc3（p.Ala58Val）突变影响了其表达，可能在遗传性BAV中起关键作用。
据我们所知，这是首次报道与遗传性BAV相关的Mybpc3杂合变异。Mybpc3突变位置与BAV之间的关系可能为理解这种疾病提供一个新的视角。
