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

• DOI: 10.1186/s12967-016-0870-4
• Publication Date: 2016-05-04T02:47:39Z
• Authors: J. K. Poninska; Z. T. Bilinska; M. Franaszczyk; E. Michalak; M. Rydzanicz; E. Szpakowski; A. Pollak; B. Milanowska; G. Truszkowska; P. Chmielewski; A. Sioma; H. Janaszek-Sitko...; A. Klisiewicz; I. Michalowska; M. Makowiecka-Ciesla; P. Kolsut; P. Stawinski; B. Foss-Nieradko; M. Szperl; J. Grzybowski; P. Hoffman; A. Januszewicz; M. Kusmierczyk; R. Ploski
• Keywords: Proband; Thoracic aortic aneurysm

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 cost-effective examination gene panels. Aim the study was define diagnostic yield NGS in 51 TAAD patients look for genotype–phenotype correlations within families TAAD. unrelated were examined by either whole exome or TruSight One panel. We analyzed rare variants 10 established thoracic aneurysms-associated genes. Whenever possible, we looked co-segregation families. Kaplan–Meier survival curve constructed compare event-free depending on genotype. Aortic events defined as acute dissection first planned surgery. In 21 found 22 variants, 6 (27.3 %) these previously reported, 16 (73.7 novel. Based segregation data, functional analysis software estimations assumed that three novel causative, nine likely causative. Remaining four classified unknown significance (2) benign (2). all, 9 (17.6 probands had a positive result when considering causative only 18 (35.3 if also included. Genotype-positive (n = 18) showed shorter mean event free (41 years, CI 35–46) than reference group, i.e. those 29) without any plausible variant identified (51 45–57, p 0.0083). This effect 'genotype-positive' group restricted 'likely causative' (p 0.0092) which further supports pathogenicity variants. The particularly low (37 27–47) among defects TGF beta signaling 0.0033 vs. group). broadens spectrum genetic its potential role prognostic factor disease.