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Lookup NU author(s): Dr Paul Brennan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): Meester JAN, Hebert A, Bastiaansen M, Rabaut L, Bastianen J, Boeckx N, Ashcroft K, Atwal PS, Benichou A, Billon C, Blankensteijn JD, Brennan P, Bucks SA, Campbell IM, Conrad S, Curtis SL, Dasouki M, Dent CL, Eden J, Goel H, Hartill V, Houweling AC, Isidor B, Jackson N, Koopman P, Korpioja A, Kraatari-Tiri M, Kuulavainen L, Lee K, Low KJ, Lu AC, McManus ML, Oakley SP, Oliver J, Organ NM, Overwater E, Revencu N, Trainer AH, Trivedi B, Turner CLS, Whittington R, Zankl A, Zentner D, Van Laer L, Verstraeten A, Loeys BL
Publication type: Article
Publication status: Published
Journal: npj Genomic Medicine
Year: 2024
Volume: 9
Issue: 1
Online publication date: 26/03/2024
Acceptance date: 15/03/2024
Date deposited: 08/04/2024
ISSN (electronic): 2056-7944
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41525-024-00413-z
DOI: 10.1038/s41525-024-00413-z
Data Access Statement: Due to restrictions in the informed consent sharing of data in secure accesscontrolled repositories is not allowed but for qualified researchers data of this study are available from the corresponding author upon reasonable request. The ClinVar accession numbers for the BGN variants reported in this study are SCV004170959 to SCV004170969, VCV000265797.1, and VCV000265798.2.
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