{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:37:01Z","timestamp":1790743021915,"version":"4.1.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"12","funder":[{"name":"Children\u2019s Discovery Institute of the Washington University School of Medicine","award":["CH-FR-2011-169"],"award-info":[{"award-number":["CH-FR-2011-169"]}]},{"name":"Children\u2019s Discovery Institute of the Washington University School of Medicine","award":["MD-II-2013-269"],"award-info":[{"award-number":["MD-II-2013-269"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL053325"],"award-info":[{"award-number":["HL053325"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL006212"],"award-info":[{"award-number":["HL006212"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams\u2013Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25\u201327 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N\u2009=\u2009104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+\/\u2212; Rag1\u2212\/\u2212 mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+\/\u2212 mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa093","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T22:14:29Z","timestamp":1589494469000},"page":"2035-2050","source":"Crossref","is-referenced-by-count":24,"title":["Whole exome sequencing in patients with Williams\u2013Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-0105","authenticated-orcid":false,"given":"Phoebe C R","family":"Parrish","sequence":"first","affiliation":[{"name":"Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell H","family":"Knutsen","sequence":"additional","affiliation":[{"name":"Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Charles J","family":"Billington","sequence":"additional","affiliation":[{"name":"Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P","family":"Mecham","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Fu","sequence":"additional","affiliation":[{"name":"Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9757-7118","authenticated-orcid":false,"given":"Beth A","family":"Kozel","sequence":"additional","affiliation":[{"name":"Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"2020073002371015900_ref1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.jpeds.2009.08.042","article-title":"Cardiovascular abnormalities, interventions, and long-term outcomes in infantile Williams syndrome","volume":"156","author":"Collins","year":"2010","journal-title":"J. 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