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Heterozygous pathogenic <jats:italic>GDF2<\/jats:italic> (encoding bone morphogenetic protein 9 (BMP9)) variants account for some (&gt;1%) adult PAH cases. Only three pediatric PAH cases, harboring homozygous or compound heterozygous variants, are reported to date. Ultra\u2010rare pathogenic <jats:italic>GDF2<\/jats:italic> variants are reported in hereditary hemorrhagic telangiectasia and overlapping disorders characterized by telangiectasias and arteriovenous malformations (AVMs). Here, we present two siblings with PAH homozygous for a <jats:italic>GDF2<\/jats:italic> mutation that impairs BMP9 proprotein processing and reduces growth factor domain availability. We confirm an absence of measurable plasma BMP9 whereas BMP10 levels are detectable and serum\u2010dependent endothelial BMP activity is evident. This contrasts with the absence of activity which we reported in two children with homozygous pathogenic <jats:italic>GDF2<\/jats:italic> nonsense variants, one with PAH and one with pulmonary AVMs, both with telangiectasias, suggesting loss of BMP10 and endothelial BMP activity in the latter may precipitate telangiectasia development. An absence of phenotype in related heterozygous <jats:italic>GDF2<\/jats:italic> variant carriers suggests incomplete penetrance in PAH and AVM\u2010related diseases, indicating that additional somatic and\/or genetic modifiers may be necessary for disease precipitation.<\/jats:p>","DOI":"10.1002\/ajmg.a.62996","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T11:15:06Z","timestamp":1666178106000},"page":"228-233","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A rare homozygous missense <scp><i>GDF2<\/i><\/scp> (<scp>BMP9<\/scp>) mutation causing <scp>PAH<\/scp> in siblings: Does <scp>BMP10<\/scp> status contribute?"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-4921","authenticated-orcid":false,"given":"Paul","family":"Upton","sequence":"first","affiliation":[{"name":"Department of Medicine, Heart and Lung Research Institute University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Richards","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonary Hypertension Service Stollery Children's Hospital  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Bates","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonary Hypertension Service Stollery Children's Hospital  Edmonton Alberta Canada"},{"name":"Department of Pediatrics University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Y.","family":"Niederhoffer","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of Alberta Hospital  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Heart and Lung Research Institute University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Christian","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonary Hypertension Service Stollery Children's Hospital  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000000329"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0608-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61743"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62584"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.165530"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01371-2018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113178"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000153798.78540.87"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1685"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201906-1141OC"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101152"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.023101"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.4103\/2045-8932.83445"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.095307"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00211-2016"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2019-1970"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2009.02.036"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22904"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9251"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01916-2018"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2008.02.009"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.10.035"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002968"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-016-0183-7"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01609-2018"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11101213"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.07.004"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0685-z"}],"container-title":["American 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