Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier
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 Asp 263 residue is... Mehr ...
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Dokumenttyp: | Artikel |
Erscheinungsdatum: | 2023 |
Reihe/Periodikum: | Frontiers in Genetics ; volume 14 ; ISSN 1664-8021 |
Verlag/Hrsg.: |
Frontiers Media SA
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Schlagwörter: | Genetics (clinical) / Genetics / Molecular Medicine |
Sprache: | unknown |
Permalink: | https://search.fid-benelux.de/Record/base-26534278 |
Datenquelle: | BASE; Originalkatalog |
Powered By: | BASE |
Link(s) : | http://dx.doi.org/10.3389/fgene.2023.1251675 |
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 Asp 263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFβ3-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.