Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier

Melanie H A M Perik; Emmanuela Govaerts; Steven Laga; Inge Goovaerts; Johan Saenen; Emeline Van Craenenbroeck; Josephina A N Meester; Ilse Luyckx; Inez Rodrigus; Aline Verstraeten; Lut Van Laer; Bart L Loeys

doi:10.3389/fgene.2023.1251675

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier

Front Genet. 2023 Aug 31:14:1251675. doi: 10.3389/fgene.2023.1251675. eCollection 2023.

Authors

Affiliations

¹ Cardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
² Department of Cardiology, AZ Dimpna, Geel, Belgium.
³ Department of Cardiac Surgery, Antwerp University Hospital, Antwerp, Belgium.
⁴ Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium.
⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.

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 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.

Keywords: Loeys–Dietz syndrome (LDS); TGFB3; connective tissue disorder; founder; genetic modifiers; thoracic aortic aneurysm and dissection (TAAD); variable expressivity.

Grants and funding

This research was largely supported by funding from the University of Antwerp (Methusalem-OEC grant “Genomed” 40709), the Research Foundation Flanders (FWO, Belgium; G042321N, G040221N, and G044720N), the Belgian Cardiac Surgery Foundation, and the Marfan Foundation. BL holds a consolidator grant from the European Research Council (Genomia: ERC-COG-2017-771945). MP is supported by a DocPro fellowship (PS ID Antigoon: 34816). BL and AV are members of the European Reference Network on rare multisystemic vascular disorders (VASCERN—project ID: 769036, partly co-funded by the European Union Third Health Programme). EC is the holder of a senior clinical investigator grant from FWO (1804320N), and IL is supported by the Outreach project (the Dutch Heart Foundation).