Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing

Miaoxian Fang,Weiping Xiong,Rong Zeng,Ruixin Fan,Changjiang Yu,Xin Li,Siyao Chen,Jian Zhuang

doi:10.1038/s41598-017-09785-y

Abstract

Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. Up to 40% of TAAD are hereditary with complex heterogeneous genetic backgrounds. Recently, next-generation sequencing (NGS) has been successfully applied to identify genetic variants in an efficient and cost-effective manner. In our study, NGS coupled with DNA target-capture array was used to screen 11 known causative genes of TAAD in 70 patients from Southern China. All the identified variants were confirmed by Sanger sequencing. We identified forty variants in 36 patients (51.4%), including three known pathogenic (7.5%), 10 likely pathogenic variants (25%, 9 in FBN1, 1 in ACTA2), and 27 variants with uncertain significance (VUS) (67.5%). Among the 27 VUS, 14 (51.9%) were in the FBN1 gene, 3 in Col5A2, 2 in ACTA2, 2 in MYH11, 2 in MYLK, 2 in SLC2A10, 1 in MSTN and 1 in SMAD3 respectively. Based on the segregation data and independent reports, five known likely pathogenic variants and four VUS were upgraded to pathogenic variant and likely pathogenic variant respectively. Our data indicate that NGS is a highly efficient genetic method for identification of pathogenic variants in TAAD patients.

Highlights

Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide
We identified forty variants in 36 patients (51.4%), including three known pathogenic (7.5%), 10 likely pathogenic variants (25%, 9 in FBN1, 1 in ACTA2), and 27 variants with uncertain significance (VUS) (67.5%)
Since identification of the very first mutation in the FBN1 in MFS5,6, causative mutations have subsequently been identified in a dozen others including COL3A1 and COL5A2 mutations associated with Ehlers-Danlos syndrome (EDS) pathogenesis[7,8], TGFBR2 mutations associated with Marfan-like syndrome[9], and TGFBR1, TGFBR2 and SMAD3 associated with LDS10–12

Summary

Introduction

Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. 11 TAAD-associated genes including ACTA2, Col3A1, Col5A2, FBN1, MSTN, MYH11, MYLK, SLC2A10, SMAD3, TGFBR1, and TGFBR2 were analyzed by NGS among 70 TAAD subjects enrolled from southern China. A previously reported missense mutation variant c.635G > A (p.Arg212Gln) in the ACTIN domain of ACTA234–36 was carried by a 48-year-old male (TAAD027) with diagnosis of Stanford A AD, ascending aortic aneurysm, and severe aortic valve insufficiency in the current study.

Results

Conclusion