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HHT is caused by a heterozygous null allele in <jats:italic>ACVRL1<\/jats:italic>, <jats:italic>ENG<\/jats:italic>, or <jats:italic>SMAD4<\/jats:italic>, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop\u2010gain variants identified in <jats:italic>GDF2<\/jats:italic> (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous <jats:italic>GDF2<\/jats:italic> sequence variant in all three affected members of one HHT family who had previously screened negative for <jats:italic>ACVRL1<\/jats:italic>, <jats:italic>ENG<\/jats:italic>, and <jats:italic>SMAD4<\/jats:italic>. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous <jats:italic>GDF2<\/jats:italic> variant is a rare cause of HHT associated with pulmonary AVMs.<\/jats:p>","DOI":"10.1002\/ajmg.a.62584","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T07:32:39Z","timestamp":1639467159000},"page":"959-964","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Identification and validation of a novel pathogenic variant in <scp><i>GDF2<\/i><\/scp> (<scp>BMP9<\/scp>) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations"],"prefix":"10.1002","volume":"188","author":[{"given":"Srimmitha","family":"Balachandar","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara J.","family":"Graves","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Shimonty","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Kerr","sequence":"additional","affiliation":[{"name":"School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Kilner","sequence":"additional","affiliation":[{"name":"School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihao","family":"Xiao","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute Imperial College London  London UK"},{"name":"Genomics England Respiratory Clinical Interpretation Partnership (GeCIP)  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Slade","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute Imperial College London  London UK"},{"name":"Genomics England Respiratory Clinical Interpretation Partnership (GeCIP)  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manveer","family":"Sroya","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Alikian","sequence":"additional","affiliation":[{"name":"Genomics England Respiratory Clinical Interpretation Partnership (GeCIP)  London UK"},{"name":"West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel","family":"Curetean","sequence":"additional","affiliation":[{"name":"West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Thomas","sequence":"additional","affiliation":[{"name":"West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust  London UK"},{"name":"Genomics England  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivienne P. 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