Publication
Title
Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome
Author
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.
Language
English
Source (journal)
Npj genomic medicine. - [London], 2016, currens
Publication
[London] : Nature Publishing Group, published in partnership with Center of Excellence in Genomic Medicine Research , 2024
ISSN
2056-7944
DOI
10.1038/S41525-024-00413-Z
Volume/pages
9 :1 (2024) , p. 1-9
Article Reference
22
ISI
001191451600001
Pubmed ID
38531898
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Genome-wide Epistasis for cardiovascular severity in Marfan Study.
Pathomechanistic study of biglycan mutations in aortopathy and skeletal dysplasia.
Using human iPSC-derived models to investigate the divergent pathomechanisms underlying biglycan-related Meester-Loeys syndrome and X-linked spondyloepimetaphyseal dysplasia.
Genomic Modifiers of Inherited Aortapathy (Genomia).
Unravelling the discriminative pathomechanisms for biglycan-related aortopathy and spondylo-epi-metaphyseal dysplasia.
Unlocking the missing heritability of thoracic aortic aneurysms.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 03.04.2024
Last edited 06.05.2024
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