Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations

Abstract

Background: Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD.

Methods: 51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery.

Results and discussion: In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group).

Conclusions: This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.

Keywords: Diagnosis; Loeys–Dietz syndrome; Marfan syndrome; Next-generation sequencing; Shprintzen–Goldberg syndrome; Thoracic aortic aneurysm and dissections.

Fig. 1

Pedigrees of families with fibrillinopathies

Fig. 2

Pedigrees of families with mutations in ACTA2, COL3A1, TGFBR1, MYH11, SKI, SMAD3, TGFBR1 and TGFBR2 genes

Fig. 3

Kaplan–Meier analysis of event free survival in TAAD in probands with variants classified as causative/likely causative vs. those without any candidate variants identified (Log-Rank Chi- square 6.97, p = 0.0083)

Fig. 4

Cardiovascular imaging study in the patient with SKI p.T20 K variant. a 2D transthoracic echocardiography of parasternal long axis demonstrated aortic root aneurysm with Valsalva sinuses diameter of 48.5 mm.; b and d 2D transthoracic echocardiography in apical four chamber view in diastole. Enlarged left ventricle and left atrium with increased mitral annular diameter of 51.4 mm; c contrast-enhanced, ECG-gated CT, volume rendering (VR) image, the aneurysm of the ascending aorta; d color flow Doppler study revealed significant mitral regurgitation due to thickened and floppy mitral valve leaflets and widened mitral annulus

Fig. 5

Cardiovascular imaging study in the patient with MYH11 p.E1840D variant. a contrast-enhanced, ECG-gated CT, multiplanar reformatted image with reconstruction parallel to aortic valve shows bicuspid aortic valve in diastole; b volume rendering (VR) image, the aneurysm of the thoracic aorta: root of 43 mm, ascending aorta- of 52 mm (maximum dimension) and aorta before the origin of brachiocephalic trunk of 40 mm, farther arch dimension is normal of 28 mm

Fig. 6

Cardiovascular imaging study in the patient with MYH11 p.R1758Q variant. a contrast-enhanced, ECG-gate CT, multiplanar reformatted images with reconstruction parallel to aortic valve show bicuspid aortic valve in diastole; b volume rendering (VR) image shows supracoronary prosthesis and dilated aortic arch. Variant anatomy: common origin of brachiocephalic and left common carotid artery. Aortic arch diameter before the anomaly of 42 mm