Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta

Abstract

PurposeThoracic aortic aneurysm/aortic dissection (TAAD) is a disorder with highly variable age of onset and phenotype. We sought to determine the prevalence of pathogenic variants in TAAD-associated genes in a mixed cohort of sporadic and familial TAAD patients and identify relevant genotype-phenotype relationships. MethodsWe used a targeted PCR and next generation sequencing-based panel for genetic analysis of 15 TAAD associated genes in 1025 unrelated TAAD cases. ResultsWe identified 49 pathogenic or likely pathogenic (P/LP) variants in 47 cases (4.9% of those successfully sequenced). Almost half of the variants were in non-syndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbour two P/LP variants. Presence of a related syndrome, younger age at presentation, family history of aortic disease and involvement of the ascending aorta increased the risk of carrying a P/LP variant. ConclusionsGiven the poor prognosis of TAAD that is undiagnosed prior to acute rupture or dissection, genetic analysis of both familial and sporadic cases of TAAD will lead to new diagnoses, more informed management and possibly reduced mortality through earlier, preclinical diagnosis in genetically determined cases and their family members.4

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

“…9,10 Indeed, high or increased diagnostic yields were observed when patients with a positive family history, with early-onset aortic disease, or with a syndromic form of TAAD were included primarily. 9,10,13 In our study, however, the diagnostic yield was not increased in patients with a positive family history. Furthermore, in three previous studies the cohorts mainly included individuals with an unambiguous TAAD phenotype; however diagnostic yields were not consistent.…”

“…Several studies on NGS applications for the molecular diagnosis of TAAD have been reported. [9][10][11][12][13][14][15][16] Taking into account only PV and LPV, the diagnostic yields were documented as 3.9% (21 genes in 102 patients analyzed), 12 4.9% (15 genes in 1025 patients analyzed), 13 8.1% (21 genes in 810 patients), 16 10.3% (10 genes in 175 patients analyzed), 11 13% (7 genes in 264 patients analyzed), 15 18.6% (11 genes in 70 patients analyzed), 14 27% (14 genes in 55 patients analyzed), 10 and 35.3% (10 genes in 51 patients analyzed). 9 In our subcohort of 71 patients with the initial diagnosis of TAAD, 12 individuals had a PV or LPV resulting in a diagnostic yield of 16.9%.…”

“…[9][10][11][12] Detection rates of causative sequence variants in 7 to 21 disease genes tested were between 3.9% and 35.3%, thus, in more than 60% of the patients, no causative variant was identified. [9][10][11][12][13][14][15][16] To date, more than 20 disease genes for aortopathies, e.g., LDS, MFS, and nonsyndromic TAAD, have been identified; 3 moreover, disease genes for several HCTDs with facultative cardiovascular manifestations, such as congenital contractural arachnodactyly (CCA), cutis laxa type IB, and arterial tortuosity syndrome, have been established. 1 With a special focus on aortopathies and vascular manifestations, we selected 32 known disease genes and genetically tested a mixed cohort of 199 patients with the clinical diagnosis of hereditary aortopathy and/or related disorder of connective tissue by using NGS technology.…”

Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

“…The significant risk factors for a pathogenic variant in patients with thoracic aortic dissection or rupture were young age (<50 years old), no history of hypertension, but strong family history of aortic aneurysm, dissection or rupture (especially involving mother, siblings and children) with estimated odds ratios ranging from 5.1 for affected siblings to 6.0 for affected children (Table 4). This is in agreement with a recent study in familial and sporadic cases of aneruysm or dissection of the thoracic aorta which demonstrated a significantly increased probability of harboring a pathogenic or likely pathogenic variant in cases which were syndromic, young (age <50), or with a known or probable family history 26 . Patients with pathogenic variants in TGFBR1/2 (Loeys-Dietz syndrome), FBN1 (Marfan syndrome), and MYH11 have a higher risk of aortic dissection and suffer more complications from aortic dissection, including death 6 .…”

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

“…Here, we established, optimized, and combined functional analyses of the adult zebrafish heart using echocardiography and MRI with a morphological characterization of the cardiac compartments and adjacent vessels using µ-CT. As a proof-of-concept, we examined alk5a/tgfbr1 mutants as TGFBR1 genetic variants in humans have been associated with aortic aneurysms and diseases of the great vessels, the diagnosis of which is most often recognized in young adults (Loeys et al, 2005;Loeys et al, 2006;Matyas et al, 2006;Weerakkody et al, 2018;Camerota et al, 2019). We show that the use of this multimodal preclinical imaging strategy allows for a robust dissection of adult zebrafish cardiac phenotypes, even in the presence of high variability between samples of the same genotype.…”