{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:56:10Z","timestamp":1790193370272,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Hereditary hemorrhagic telangiectasia (HHT) is a near-fully penetrant autosomal dominant disorder characterized by nosebleeds, anemia, and arteriovenous malformations. The great majority of HHT cases are caused by heterozygous loss-of-function mutations in\n                      <jats:italic toggle=\"yes\">ACVRL1<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">ENG<\/jats:italic>\n                      , which encode proteins that function in bone morphogenetic protein signaling. HHT prevalence is estimated at 1 in 5000 and is accordingly classified as rare. However, HHT is suspected to be underdiagnosed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      To estimate the true prevalence of HHT, we summed allele frequencies of predicted pathogenic variants in\n                      <jats:italic toggle=\"yes\">ACVRL1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ENG<\/jats:italic>\n                      using 3 methods. For method 1, we included Genome Aggregation Database (gnomAD v4.1) variants with ClinVar annotations of pathogenic or likely pathogenic, plus unannotated variants with a high probability of causing disease. For method 2, we evaluated all\n                      <jats:italic toggle=\"yes\">ACVRL1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ENG<\/jats:italic>\n                      gnomAD variants using threshold filters based on accessible in silico pathogenicity prediction algorithms. For method 3, we developed a machine learning-based classification system to improve the classification of missense variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We calculated an HHT prevalence of between 2.1 in 5000 and 11.9 in 5000, or 2 to 12\u00d7 higher than current estimates. Application of our machine learning-based classification method revealed missense variants as the greatest contributor to pathogenic allele frequency and similar HHT prevalence across genetic ancestries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our results support the notion that HHT is underdiagnosed and that HHT prevalence may be above the threshold of a rare disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.124.005061","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:00:14Z","timestamp":1758186014000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in\n                    <i>ENG<\/i>\n                    and\n                    <i>ACVRL1<\/i>"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2870-1074","authenticated-orcid":true,"given":"Anthony R.","family":"Anzell","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, PA (A.R.A., C.M.W., B.D., J.C.C., B.L.R.)."},{"name":"Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, PA (A.R.A., B.L.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2377-8556","authenticated-orcid":true,"given":"Carter","family":"M. White","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, PA (A.R.A., C.M.W., B.D., J.C.C., B.L.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3578-6547","authenticated-orcid":true,"given":"Brenda","family":"Diergaarde","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, PA (A.R.A., C.M.W., B.D., J.C.C., B.L.R.)."},{"name":"UPMC Hillman Cancer Center, Pittsburgh, PA (B.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-0833","authenticated-orcid":true,"given":"Jenna C.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, PA (A.R.A., C.M.W., B.D., J.C.C., B.L.R.)."},{"name":"Department of Biostatistics and Health Data Science, University of Pittsburgh, PA (J.C.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1250-1705","authenticated-orcid":true,"given":"Beth L.","family":"Roman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, PA (A.R.A., C.M.W., B.D., J.C.C., B.L.R.)."},{"name":"Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, PA (A.R.A., B.L.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00585-z"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1294-345"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-189"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0775-8"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.973964"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.8.527"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320520232"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1999.00398.x"},{"key":"e_1_3_3_10_2","first-page":"221","article-title":"Prevalence of hereditary hemorrhagic telangiectasia in a medical care program organization in Buenos Aires, Argentina.","volume":"84","author":"Serra MM","year":"2024","unstructured":"Serra MM, Papi M, Serrano C. 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