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

Abstract

BackgroundThoracic 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.Methods51 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 discussionIn 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).ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0870-4) contains supplementary material, which is available to authorized users.

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

“…In this cohort of 810 patients, a pathogenic or likely pathogenic variant was identified in 66 patients (8.1%). Overall, we identified a relatively low number of pathogenic or likely pathogenic variants in our H-TAD cohort compared to pre-vious studies that identified mutations in 10.3% to 35.5% (Campens et al, 2015;Lerner-Ellis et al, 2014;Poninska et al, 2016;Proost et al, 2015;Wooderchak-Donahue et al, 2015;Ziganshin et al, 2015). This wide range is likely to be explained by differences in clinical and demographic characteristics of the study populations and different inclusion criteria used for genetic testing.…”

Large gene panel sequencing in clinical diagnostics—results from 501 consecutive cases

“…Recently, a large cohort from Saudi‐Arabia sequenced by custom large gene panels was reported to yield 43% of clinical diagnostic findings in a consanguineous population . In addition, large gene panels have been used in disease‐specific study groups . To our knowledge, however, there have been no published reports on the clinical utility of large gene panel sequencing in a large unselected diagnostic cohort from an outbred population.…”

“…11 In addition, large gene panels have been used in disease-specific study groups. 12,13 To our knowledge, however, there have been no published reports on the clinical utility of large gene panel sequencing in a large unselected diagnostic cohort from an outbred population. In this report, we aim to share our experience from the first 1.5 years of large gene panel sequencing in a clinical setting, which involved 501 cases.…”

Exploring the genetic pathogenicity of aortic dissection from 72 Han Chinese individuals using next‐generation sequencing

“…While there are many risk factors, including male sex, age>65 years, hypertension, smoking, and syndromic disorders (such as Marfan syndrome and Loeys‐Dietz syndrome), genetic causes may be the primary cause . The identification of specific genotypes in AD could help improve the surveillance and treatment of patients, establish an anticipated risk stratification and prognosis, and perform cascade screenings for other family members at risk, all with the aim of reducing morbidity and mortality . In this study, we sequenced 142 AD‐associated genes from 72 patients with AD.…”