{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T10:01:26Z","timestamp":1780308086007,"version":"3.54.0"},"reference-count":28,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in\n                    <jats:italic>ENG<\/jats:italic>\n                    ,\n                    <jats:italic>ACVRL1<\/jats:italic>\n                    ,\n                    <jats:italic>SMAD4,<\/jats:italic>\n                    or\n                    <jats:italic>GDF2<\/jats:italic>\n                    . In contrast,\n                    <jats:italic>BMPR2<\/jats:italic>\n                    variants are well\u2010established in heritable pulmonary arterial hypertension (PAH), but their relationship to PAVMs remains poorly understood. We report the case of a 41\u2010year\u2010old woman with an incidentally discovered PAVM, initially treated with embolization and subsequent surgical resection. She remained asymptomatic for several years until progressive exertional dyspnea led to a diagnosis of severe precapillary PAH. Genetic testing identified a heterozygous\n                    <jats:italic>BMPR2<\/jats:italic>\n                    splice\u2010site variant (c.967\u2009+\u20095G&gt;A), previously reported in a PAH cohort but currently classified as a variant of uncertain significance. This report is notable for the delayed evolution from isolated PAVM to PAH in the context of a\n                    <jats:italic>BMPR2<\/jats:italic>\n                    variant, raising the possibility of a mechanistic link outside the canonical HHT pathway. We review published reports of\n                    <jats:italic>BMPR2<\/jats:italic>\n                    \u2010associated PAVMs, some of which include subtle HHT\u2010like features, such as mucocutaneous telangiectases and epistaxis, despite negative testing for classical HHT genes. These observations suggest a potential phenocopy vascular syndrome driven by disruption of the shared bone morphogenetic protein 9 (BMP9)\u2010ALK1 signaling axis. We also discuss the implications of sotatercept, a transforming growth factor\u2010beta (TGF\u2010\u03b2) superfamily ligand trap, which in this case was associated with symptomatic improvement and stable shunt burden. These findings contribute to the emerging recognition of atypical vascular phenotypes in\n                    <jats:italic>BMPR2<\/jats:italic>\n                    variant carriers, particularly those presenting with PAVMs in the absence of HHT. It highlights the importance of considering genetic testing in isolated AVM presentations, as well as the need for longitudinal surveillance and mechanistic investigation into overlapping TGF\u2010\u03b2\/BMP signaling disorders.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70109","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:57:14Z","timestamp":1772989034000},"page":"1682-1690","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>BMPR2<\/i>\n                    <\/scp>\n                    Splice\u2010Site Variant in a Patient With Pulmonary Arteriovenous Malformation and Delayed\u2010Onset Pulmonary Arterial Hypertension: A Case Report and\u00a0Mechanistic Phenocopy Hypothesis"],"prefix":"10.1002","volume":"200","author":[{"given":"Akshay","family":"Mathavan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3496-2542","authenticated-orcid":false,"given":"Akash","family":"Mathavan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urszula","family":"Krekora","sequence":"additional","affiliation":[{"name":"College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga Romina Gomez","family":"Rojas","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh","family":"Huynh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mason","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Dinh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S.","family":"Zumberg","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4729-028X","authenticated-orcid":false,"given":"Jeb","family":"Justice","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-1680","authenticated-orcid":false,"given":"Ali","family":"Ataya","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmcr.2021.101352"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.2025.211.Abstracts.A6504"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.6515\/ACS.202207_38(4).20220210A"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.309930"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.7326\/M20\u20101443"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13247812"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2013.08.003"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2024.02.090"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2000348"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000557"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2213558"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac237"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024277"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2023.04.031"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.10.036"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00072911"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061927"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202501\u20100056RL"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds073"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacr.2024.02.028"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32468"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1183\/09059180.00011102"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096\u20108628(20000306)91:1<66::AID\u2010AJMG12>3.0.CO;2\u2010P"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00126207"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20160531"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201311\u20102019IM"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.124.034726"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70109","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70109","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T09:07:29Z","timestamp":1780304849000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,8]]},"references-count":28,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/ajmg.a.70109"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70109","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,8]]},"assertion":[{"value":"2025-07-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}