Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome

Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate se...

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Bibliographic Details
Published in:	Journal of the American Heart Association Vol. 13; no. 3; p. e031377
Main Authors:	Liu, Delong, Billington, Jr, Charles J, Raja, Neelam, Wong, Zoe C, Levin, Mark D, Resch, Wulfgang, Alba, Camille, Hupalo, Daniel N, Biamino, Elisa, Bedeschi, Maria Francesca, Digilio, Maria Cristina, Squeo, Gabriella Maria, Villa, Roberta, Parrish, Pheobe C R, Knutsen, Russell H, Osgood, Sharon, Freeman, Joy A, Dalgard, Clifton L, Merla, Giuseppe, Pober, Barbara R, Mervis, Carolyn B, Roberts, Amy E, Morris, Colleen A, Osborne, Lucy R, Kozel, Beth A
Format:	Journal Article
Language:	English
Published:	England John Wiley and Sons Inc 06-02-2024 Wiley
Subjects:	adaptive/innate immune system elastin (ELN) extreme phenotype Original Research pathway analysis supravalvar aortic stenosis Williams–Beuren syndrome elastin (ELN) supravalvar aortic stenosis adaptive/innate immune system pathway analysis Williams–Beuren syndrome extreme phenotype
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Summary:	Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes ( and ) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.123.031377 This article was sent to Jacquelyn Y. Taylor, PhD, PNP‐BC, RN, FAHA, FAAN, Guest Editor, for review by expert referees, editorial decision, and final disposition. Preprint posted on MedRxiv September 22, 2022. doi: https://doi.org/10.1101/2022.09.21.22280107. For Sources of Funding and Disclosures, see page 13.
ISSN:	2047-9980 2047-9980
DOI:	10.1161/JAHA.123.031377