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. 2018 Nov;20(11):1414-1422.
doi: 10.1038/gim.2018.27. Epub 2018 Mar 15.

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

Ruwan Weerakkody  1   2   3 , David Ross  2 , David A Parry  2 , Bulat Ziganshin  4 , Jana Vandrovcova  5 , Piyush Gampawar  2 , Abdulshakur Abdullah  1 , Jennifer Biggs  1 , Julia Dumfarth  4 , Yousef Ibrahim  3 ; Yale Aortic Institute Data and Repository Team; Colin Bicknell  3 , Mark Field  6 , John Elefteriades  4 , Nick Cheshire  3 , Timothy J Aitman  7   8   9
Affiliations

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

Ruwan Weerakkody et al. Genet Med. 2018 Nov.

Abstract

Purpose: Thoracic 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.

Methods: We used a targeted polymerase chain reaction and next-generation sequencing-based panel for genetic analysis of 15 TAAD-associated genes in 1,025 unrelated TAAD cases.

Results: We 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 nonsyndromic cases with no known family history of aortic disease. Twenty-five variants were within FBN1 and two patients were found to harbor 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.

Conclusion: Given 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.

Keywords: FBN1; TAAD genetics; high-throughput DNA sequencing; sporadic TAAD; thoracic aortic aneurysm/aortic dissection.

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Conflict of interest statement

Conflict of Interest

Tim Aitman reports grants from Wellcome, grants from National Institute for Health Research, grants from UK Medical Council, personal fees from Illumina, during the conduct of the study; personal fees from AstraZeneca, outside the submitted work.

Colin Bicknell reports personal fees from Medtronic, personal fees from Bolton Medical, non-financial support from Vascutek, non-financial support from Gore, outside the submitted work.

Figures

Figure 1
Figure 1
Numbers of pathogenic or likely pathogenic (P/LP) variants identified by gene across both the Yale and UK cohorts. Percentages shown are the overall proportion of P/LP variants for each gene.
Figure 2
Figure 2
Influence of variant type and diagnosis of Marfan syndrome on age of diagnosis. In cases with more than one P/LP variant or VUS, only the most damaging was included in this analysis. Age distribution and impact of age on variant type in whole cohort (a, b), and in non-Marfan patients (c, d).
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