Exploring The Genetic Differences Between Stanford A And Stanford B Aortic Dissection

【Background】 The etiology of aortic dissection(AD)is complex with rapid development and high mortality.It is one of the most important cardiovascular diseases that threatens human life as well as the common causes of sudden cardiac death in forensic practice.A lot of genes are associated with AD.Gene mutations are predispose to AD and are important pathogenic factors of it.It is worth noting that the majority of AD cases in forensic sudden death are Stanford A AD.Therefore,whether there are genetic differences between Stanford A and Stanford B AD cases,whether there are genetic differences that lead to diverse prognosis and sudden death rates of Stanford A and Stanford B AD.These problems still unclear.It is of great significance to explore the genetic characteristics of Stanford A AD(more severe type)for forensic practice,early clinical intervention and prevention for high-risk populations.In this project,72 unrelated Han Chinese individuals with AD(57 Stanford A AD and 15 Stanford B AD)were tested by whole-exome sequencing and 142 AD related genes were selected for analysis to explore the relationship between Stanford A and Stanford B AD,to broaden the pathogenic gene spectrum of AD in Chinese population,as well as to reported novel variants in AD related genes.【Objective】 The aims of our study are exploring whether there is genetic differences between Stanford A AD and Stanford B AD,broadening the pathogenic gene spectrum of AD in Chinese population,and reporting novel variants in AD related genes.【Methods】 ⑴ The establishment of a biogenetic specimen bank: Relying on the Department of Forensic Medicine and the Affiliated Hospital of Tongji Medical College of Huazhong University of Science and Technology,blood/tissue samples of deceased and clinical patients with AD in the Han population were collected and kept for future use.⑵ selection of case group and control group:(1)72 unrelated AD cases were randomly selected.(2)The genomic sequences of 2573 healthy Han people were selected as the control group.⑶ Extraction of genomic DNA: using TIANamp blood DNA Kit(Tiangen,DP318)to extract genomic DNA from 72 AD cases.⑷ Whole exome sequencing: 72 AD cases were tested by whole exome sequencing.⑸ Bioinformatic and statistical analysis: pathogenic and likely pathogenic variants in 142 AD related genes were selected to analyse the distribution characteristics and differences.【Results】 ⑴ 58 positive(pathogenic and likely pathogenic)variants were detected and identified in this study.The genetic diagnosis in this study was 54.2%(39/72),of which 27 positive variants were novel.⑵ The average onset age in "genotype-positive AD group" is younger than that in the "genotype-negative AD group",and the "group with multiple positive variants" has a shorter survival than the "genotype-negative AD group".⑶ Positive variants in ACTA2 gene were idetified in one Stanford A AD,and positive variants in the MYH11,MYH14,and MYLK genes were detected in three Stanford B AD.That is,"smooth muscle cell contraction " positive genes rates in Stanford A and Stanford B AD were 20.0% and 1.8%(3/15 vs.1/57,P = 0.027),respectively.⑷ Of 45 COL family genes,27 positive variants from 18 genes were distributed in 21 Stanford A AD and 1 Stanford B AD.The positive genes rates were 36.8% and 6.7%(21 / 57 vs.1/15,P = 0.028),respectively.⑸ FBN1 positive variants were detected in 10 AD cases,of which 7 were located in the cb EGF domain(5 Stanford A AD,2 Stanford B AD),and 3 wer in the TGFBP domain(2 Stanford A AD,1 Stanford B AD).【Conclusion】 ⑴ AD with positive variants had a younger onset age,AD individuals with multiple positive variants had a shorter survival.⑵ positive variants in COL family genes were detected more frequenctly in Stanford A AD while positive variants in SMC genes were frequently in Stanford B AD.⑶ No matter Stanford A or Stanford B AD,FBN1 was the most frequently gene.