{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:00:14Z","timestamp":1789693214567,"version":"4.0.1"},"reference-count":26,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Approximately 35% of patients with type 1 von Willebrand disease (VWD) do not have a known pathogenic variant in the von Willebrand factor (VWF) gene. We aimed to understand the impact of VWF coding variants on VWD risk and VWF antigen (VWF:Ag) levels, studying 527 patients with low VWF and VWD and 210 healthy controls. VWF sequencing was performed and VWF:Ag levels assayed. A combined annotation-dependent depletion (CADD) score &amp;gt;20 was used as a predicted pathogenicity measure. The number of rare nonsynonymous VWF variants significantly predicted VWF:Ag levels (P = 1.62 \u00d7 10\u221221). There was an association between average number of rare nonsynonymous VWF variants with VWD type 1 (P = 2.4 \u00d7 10\u221213) and low VWF (P = 1.6 \u00d7 10\u221227) compared with healthy subjects: type 1 subjects possessed on average &amp;gt;2 times as many rare variants as those with low VWF and 8 times as many as healthy subjects. The number of rare nonsynonymous variants significantly predicts VWF:Ag levels even after controlling for presence of a variant with a CADD score &amp;gt;20 or a known pathogenic variant in VWF (P = 2.7 \u00d7 10\u221214). The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD &amp;gt;20 are both significantly associated with VWF levels. The association with rare nonsynonymous variants holds even when controlling for known pathogenic variants, suggesting that additional variants, in VWF or elsewhere, are associated with VWF:Ag levels. Patients with higher VWF:Ag levels with fewer rare nonsynonymous VWF gene variants could benefit from next-generation sequencing to find the cause of their bleeding.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2020009999","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T07:09:59Z","timestamp":1612854599000},"page":"3277-3283","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":22,"title":["von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the\n                    <i>VWF<\/i>\n                    gene"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-3809","authenticated-orcid":false,"given":"Brooke","family":"Sadler","sequence":"first","affiliation":[{"name":"1Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela A.","family":"Christopherson","sequence":"additional","affiliation":[{"name":"2Versiti Blood Research Institute, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3884-5776","authenticated-orcid":false,"given":"Gabe","family":"Haller","sequence":"additional","affiliation":[{"name":"3Department of Neurosurgery, School of Medicine, Washington University in St Louis, St Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert R.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"2Versiti Blood Research Institute, Milwaukee, WI"},{"name":"4Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1461-2871","authenticated-orcid":false,"given":"Jorge","family":"Di Paola","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"3","key":"2026072111213445000_bib1","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.thromres.2015.07.014","article-title":"Severe, recessive type 1 is a discrete form of von Willebrand disease: the lesson learned from the c.1534-3C&gt;A von Willebrand factor mutation","volume":"136","author":"Casonato","year":"2015","journal-title":"Thromb Res"},{"issue":"2","key":"2026072111213445000_bib2","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1073\/pnas.1219885110","article-title":"Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association","volume":"110","author":"Desch","year":"2013","journal-title":"Proc Natl Acad Sci 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