Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.
Journal
NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193
Informations de publication
Date de publication:
26 Mar 2024
26 Mar 2024
Historique:
received:
01
12
2023
accepted:
15
03
2024
medline:
27
3
2024
pubmed:
27
3
2024
entrez:
27
3
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38531898
doi: 10.1038/s41525-024-00413-z
pii: 10.1038/s41525-024-00413-z
doi:
Types de publication
Journal Article
Langues
eng
Pagination
22Subventions
Organisme : Universiteit Antwerpen (University of Antwerp)
ID : Methusalem-OEC grant "Genomed" - 40709
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : G040221N, G044720N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 12X8520N, 12AO124N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 11PM524N
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : ERC-COG-2017-771945
Organisme : U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ID : K08-HD111688
Informations de copyright
© 2024. The Author(s).
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