Aortic dissection(AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted nextgeneration sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25%(430/702) of patients. In these patients, 34.88%(150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72%(335/702) of patients. Importantly, we identified 94 lossof-function(LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls(P=1.34×10^(-4)). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.
Aortic dissection(AD) is a devastating,heterogeneous condition of aorta.The homeostasis between collagens and matrix metalloproteases(MMPs)/tissue inhibitors of MMPs(TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta.However,our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited.We analyzed all yet known coding human genes of collagens(45 genes),MMPs/TIMPs(27genes) in 702 sporadic AD patients and in 163 matched healthy controls,by using massively targeted next-generation and Sanger sequencing.To define the pathogenesis of potential disease-causing candidate genes,we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats.We identified 257 pathogenic or likely pathogenic variants which involved 88.89%(64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05%(218/702) sporadic AD patients.In them,84.86%patients(185/218) carried one variant,12.84%two variants and 2.30%more than two variants.Importantly,we identified 52 novel probably pathogenic loss-of-function(LOF) variants(20 nonsense,16 frameshift,14 splice sites,one stop-loss,one initiation codon) in 11.06%(50/452) AD patients,which were absent in 163controls(P=2.5×10^(-5)).Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems.The Col5α2^(-/-) rats manifested growth retardation and aortic dysplasia.Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.
