A novel TGFβR2 splice variant in patient with aortic aneurysm and family history for aortic dissection: a case report

Abstract

We report the clinical presentation and genetic screening of a 31-year-old man with dilatation of the aortic root and ascending aorta and a positive family history for aortic dissection and sudden death. A novel heterozygous variant in a splice acceptor site (c.1600-1G>T) of TGFβR2 gene was identified by using a targeted multi-gene panel analysis. Bioinformatics tools predicted that the c.1600-1G>T variant is pathogenic by altering acceptor splice site at − 1 position affecting pre-mRNA splicing. These data confirm that the diverging splicing in the TGF-β pathway genes may be an important process in aneurismal disease and emphasize the utility of genetic sequencing in the identification of high-risk patients for a more patient’s management able to improve outcomes and minimize costs for the care of patients with heritable thoracic aortic aneurysm and dissection.

Executive summary

• Heritable thoracic aortic aneurysms (TAA) refer to a group of genetic connective tissue disorders affecting the aorta, typically asymptomatic, leading to an acute aortic dissection with life-threatening complications including sudden death.

• Mutations in the genes encoding the TGF-b receptors (TGFBR1 and TGFBR2) have been identified as a cause of familial TAA and dissections. Nevertheless, the effects of individual gene variants are not completely understood.

• The screening of a targeted multi-gene panel reveals a heterozygous novel variant in the TGFβR2 gene in a 31-year-old man with dilatation of the aortic root and ascending aorta and a positive family history for aortic dissection and sudden death.

• The novel heterozygous TGFβR2 variant c.1600-1G>T was found within the acceptor splice site of exon 7. Varsome and Franklin database classified the variant as “likely pathogenetic”.

• Splicing evaluation programs predicted that the c.1600-1G>T variant is pathogenic since affects the pre-mRNA splicing by the altering acceptor splice site at − 1 position.

• Differential splicing is a common feature of TAA formation, and in particular, the diverging splicing in the TGF-β pathway genes may be an important process in aneurismal disease.

• Utility of genetic screening in the identification of high-risk patients with heritable TAA for a more personalized management pointing at improving outcomes and minimize care costs.

Keywords: :

• heritable thoracic aortic aneurysms
• mutation
• splice acceptor site
• transforming growth factor-beta
• TGFβR2

Author contributions

Material preparation, data collection and analysis were performed by C Vecoli, I Foffa, S Vittorini and N Botto. Clinical and imaging analysis was performed by A Esposito, S Costa, V Piagneri, P Festa and L Ait-Ali. The first draft of the manuscript was written by C Vecoli and I Foffa. All authors commented on previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Figure 3A–C.