{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T06:23:44Z","timestamp":1787379824382,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":232,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171701"],"award-info":[{"award-number":["82171701"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder primarily caused by pathogenic variants in the\n                      <jats:italic>ENG<\/jats:italic>\n                      gene, leading to clinical manifestations including pulmonary arteriovenous malformation (PAVM), recurrent spontaneous nosebleeds, and other related symptoms. This study is aimed at investigating the clinical manifestations of members in four HHT1 families with PAVMs and analyze novel\n                      <jats:italic>ENG<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed on the probands and their family members from Families 1 to 4. Bioinformatics programs were utilized to assess the pathogenicity of the candidate variants. Additionally, an in vitro minigene assay was conducted to examine the impact of the variant in Family 2 on RNA splicing, and Western blot was employed to validate the impact of the variant on protein expression and modification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four\n                      <jats:italic>ENG<\/jats:italic>\n                      variants were identified: c.613del (exon 5), c.1428 + 2\u2009T &gt; C (intron 11), c.1498dup (exon 12), and c.322del (exon 3). The splice\u2010site variant c.1428 + 2\u2009T &gt; C, which has been reported as pathogenic in ClinVar, leads to aberrant\n                      <jats:italic>ENG<\/jats:italic>\n                      mRNA splicing with exon 11 skipping, resulting in a shorter protein (p.Lys438_Gln476del) with impaired glycosylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The splice\u2010site variant c.1428 + 2\u2009T &gt; C caused aberrant ENG mRNA splicing, leading to exon 11 skipping and producing a shorter protein with abnormal glycosylation (p.Lys438_Gln476del). The variants identified in Families 1, 3, and 4 (c.613delC, c.1498dupC, and c.322delG) are all frameshift variants that lead to premature termination of translation. This study expands the spectrum of\n                      <jats:italic>ENG<\/jats:italic>\n                      variants and provides insights into the pathogenesis of HHT1. These findings offer guidance for the early diagnosis for families affected by HHT1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/8307860","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T05:38:23Z","timestamp":1787377103000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Study on the Clinical Phenotypes and Genetic Analysis of\n                    <i>ENG<\/i>\n                    Variants in Four Hereditary Hemorrhagic Telangiectasia Type 1 Families"],"prefix":"10.1155","volume":"2026","author":[{"given":"Yujing","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingmin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangjie","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2970-8400","authenticated-orcid":false,"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4006-9808","authenticated-orcid":false,"given":"Chang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2017-210764"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2019-231981"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMicm0803889"},{"key":"e_1_2_9_4_2","first-page":"2321","article-title":"Fistulectomy as a Surgical Option for Pulmonary Arteriovenous Malformation","volume":"122","author":"Zhang S. 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