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 an...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1251675/full |
| _version_ | 1797730828564824064 |
|---|---|
| author | Melanie H. A. M. Perik Emmanuela Govaerts Steven Laga Inge Goovaerts Inge Goovaerts Johan Saenen Emeline Van Craenenbroeck Josephina A. N. Meester Ilse Luyckx Ilse Luyckx Inez Rodrigus Aline Verstraeten Lut Van Laer Bart L. Loeys Bart L. Loeys |
| author_facet | Melanie H. A. M. Perik Emmanuela Govaerts Steven Laga Inge Goovaerts Inge Goovaerts Johan Saenen Emeline Van Craenenbroeck Josephina A. N. Meester Ilse Luyckx Ilse Luyckx Inez Rodrigus Aline Verstraeten Lut Van Laer Bart L. Loeys Bart L. Loeys |
| author_sort | Melanie H. A. M. Perik |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:49:54Z |
| format | Article |
| id | doaj.art-a774750e83bd4f27bb0ab640be8f5b7d |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-03-12T11:49:54Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-a774750e83bd4f27bb0ab640be8f5b7d2023-08-31T10:17:41ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-08-011410.3389/fgene.2023.12516751251675Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifierMelanie H. A. M. Perik0Emmanuela Govaerts1Steven Laga2Inge Goovaerts3Inge Goovaerts4Johan Saenen5Emeline Van Craenenbroeck6Josephina A. N. Meester7Ilse Luyckx8Ilse Luyckx9Inez Rodrigus10Aline Verstraeten11Lut Van Laer12Bart L. Loeys13Bart L. Loeys14Cardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumDepartment of Cardiology, AZ Dimpna, Geel, BelgiumDepartment of Cardiac Surgery, Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumDepartment of Cardiology, Antwerp University Hospital, Antwerp, BelgiumDepartment of Cardiology, Antwerp University Hospital, Antwerp, BelgiumDepartment of Cardiology, Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Cardiac Surgery, Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumCardiogenomics and Functional Genomics, Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, BelgiumDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, NetherlandsBackground: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.https://www.frontiersin.org/articles/10.3389/fgene.2023.1251675/fullLoeys–Dietz syndrome (LDS)TGFB3thoracic aortic aneurysm and dissection (TAAD)foundergenetic modifiersconnective tissue disorder |
| spellingShingle | Melanie H. A. M. Perik Emmanuela Govaerts Steven Laga Inge Goovaerts Inge Goovaerts Johan Saenen Emeline Van Craenenbroeck Josephina A. N. Meester Ilse Luyckx Ilse Luyckx Inez Rodrigus Aline Verstraeten Lut Van Laer Bart L. Loeys Bart L. Loeys Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier Frontiers in Genetics Loeys–Dietz syndrome (LDS) TGFB3 thoracic aortic aneurysm and dissection (TAAD) founder genetic modifiers connective tissue disorder |
| title | Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier |
| title_full | Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier |
| title_fullStr | Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier |
| title_full_unstemmed | Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier |
| title_short | Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier |
| title_sort | variable clinical expression of a belgian tgfb3 founder variant suggests the presence of a genetic modifier |
| topic | Loeys–Dietz syndrome (LDS) TGFB3 thoracic aortic aneurysm and dissection (TAAD) founder genetic modifiers connective tissue disorder |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1251675/full |
| work_keys_str_mv | AT melaniehamperik variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT emmanuelagovaerts variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT stevenlaga variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT ingegoovaerts variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT ingegoovaerts variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT johansaenen variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT emelinevancraenenbroeck variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT josephinaanmeester variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT ilseluyckx variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT ilseluyckx variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT inezrodrigus variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT alineverstraeten variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT lutvanlaer variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT bartlloeys variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier AT bartlloeys variableclinicalexpressionofabelgiantgfb3foundervariantsuggeststhepresenceofageneticmodifier |