{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:29:08Z","timestamp":1793831348295,"version":"4.6.1"},"reference-count":51,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2013,3,19]]},"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR\/DF). Mutations in the major PAH gene,\n                      <jats:italic>BMPR2<\/jats:italic>\n                      , were reported to cause PAH in only 10\u201316% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR\/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2.\n                      <jats:italic>TBX2<\/jats:italic>\n                      and\n                      <jats:italic>TBX4<\/jats:italic>\n                      were selected from this area as candidate genes and sequenced in all 20 children. After identifying\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations in these children, we subsequently sequenced\n                      <jats:italic>TBX4<\/jats:italic>\n                      in a cohort of 49 adults with PAH. Because\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations are known to cause small patella syndrome (SPS), all patients with newly detected\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations (n=3) or\n                      <jats:italic>TBX4<\/jats:italic>\n                      -containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These data indicate that\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult\n                      <jats:italic>TBX4<\/jats:italic>\n                      mutation carriers is low.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-101152","type":"journal-article","created":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T20:20:55Z","timestamp":1366143655000},"page":"500-506","source":"Crossref","is-referenced-by-count":216,"title":["<i>TBX4<\/i>\n                    mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension"],"prefix":"10.1136","volume":"50","author":[{"given":"Wilhelmina S","family":"Kerstjens-Frederikse","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernie M H F","family":"Bongers","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus T R","family":"Roofthooft","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, National Referral Center for Pediatric Pulmonary Hypertension, Center for Congenital Heart Diseases, Beatrix Children\u2019s Hospital, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M","family":"Leter","sequence":"additional","affiliation":[{"name":"Department of Genetics, VU Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Menno","family":"Douwes","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, National Referral Center for Pediatric Pulmonary Hypertension, Center for Congenital Heart Diseases, Beatrix Children\u2019s Hospital, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Van Dijk","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Vonk-Noordegraaf","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, VU Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista K","family":"Dijk-Bos","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lies H","family":"Hoefsloot","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke S","family":"Hoendermis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Center for Congenital Heart Diseases University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan J P","family":"Gille","sequence":"additional","affiliation":[{"name":"Department of Genetics, VU Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Sikkema-Raddatz","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M W","family":"Hofstra","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf M F","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, 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