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Title: | Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome | Authors: | Meester, Josephina A. N. Hebert, Anne Bastiaansen, Maaike Rabaut, Laura Bastianen, Jarl Boeckx, Nele Ashcroft, Kathryn Atwal, Paldeep S. Benichou, Antoine Billon, Clarisse Blankensteijn, Jan D. Brennan, Paul Bucks, Stephanie A. Campbell, Ian M. Conrad, Solene Curtis, Stephanie L. Dasouki, Majed Dent, Carolyn L. Eden, James Goel, Himanshu Hartill, Verity Houweling, Arjan C. Isidor, Bertrand Jackson, Nicola KOOPMAN, Pieter Korpioja, Anita Kraatari-Tiri, Minna Kuulavainen, Liina Lee, Kelvin Low, Karen J. Lu, Alan C. McManus, Morgan L. Oakley, Stephen P. Oliver, James Organ, Nicole M. Overwater, Eline Revencu, Nicole Trainer, Alison H. Trivedi, Bhavya Turner, Claire L. S. Whittington, Rebecca Zankl, Andreas Zentner, Dominica Van Laer , Lut Verstraeten , Aline Loeys, Bart L. |
Issue Date: | 2024 | Publisher: | NATURE PORTFOLIO | Source: | npj Genomic Medicine, 9 (1) (Art N° 22) | Abstract: | Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN. | Notes: | Loeys, BL (corresponding author), Univ Antwerp, Ctr Med Genet, Antwerp, Belgium.; Loeys, BL (corresponding author), Antwerp Univ Hosp, Antwerp, Belgium.; Loeys, BL (corresponding author), Radboud Univ Nijmegen, Dept Clin Genet, Med Ctr, Nijmegen, Netherlands. bart.loeys@uantwerpen.be |
Document URI: | http://hdl.handle.net/1942/42820 | e-ISSN: | 2056-7944 | DOI: | 10.1038/s41525-024-00413-z | ISI #: | 001191451600001 | Rights: | The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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