Publication
Title
Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier
Author
Abstract
Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation.Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGF beta 3-cytokine.Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm).Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.
Language
English
Source (journal)
Frontiers in genetics. - Place of publication unknown
Publication
Place of publication unknown : publisher unknown , 2023
ISSN
1664-8021
DOI
10.3389/FGENE.2023.1251675
Volume/pages
14 (2023) , p. 1-7
Article Reference
1251675
ISI
001093067900001
Pubmed ID
37719708
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Molecular exploration of a new aortopathy syndrome with strong potential to inform the pathogenesis and treatment of heritable thoracic aortic aneurysm.
Genome-wide Epistasis for cardiovascular severity in Marfan Study.
Pathomechanistic study of biglycan mutations in aortopathy and skeletal dysplasia.
Genomic Modifiers of Inherited Aortapathy (Genomia).
Cutting-edge exploration of the genetic modifiers underlying variable aortopathy expressivity.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 04.12.2023
Last edited 08.12.2023
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