{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:59:45Z","timestamp":1791295185136,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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":["Pediatric Pulmonology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      To describe the variant class associations with phenotype, natural history, treatment response, and outcomes in children with\n                      <jats:italic>TBX4<\/jats:italic>\n                      \u2010associated pulmonary hypertension (\n                      <jats:italic>TBX4<\/jats:italic>\n                      \u2010PH).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Retrospective cohort analysis of children &lt;\u200918 years referred to the National Paediatric Pulmonary Hypertension Service between 2001 and 2025.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty\u2010one children were identified carrying either a copy number variant (CNV group\u2009=\u200910) encompassing\n                      <jats:italic>TBX4<\/jats:italic>\n                      or a single nucleotide variant (SNV group\u2009=\u200911). Distinct phenotypic differences were observed between variant classes. Children in the CNV group were referred at a younger age (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03), more frequently had prolonged oxygen dependence from birth (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), more severe lung disease (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and cyanosis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04), congenital heart disease (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03), neurodevelopmental disorders (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), and deafness (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01). Children in the SNV group were less likely to have any lung disease (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03). Histopathology from five children (CNV\u2009=\u20093, SNV\u2009=\u20092) demonstrated predominantly lung growth abnormalities with variable pulmonary vascular remodeling. Twenty of 21 (95%) children received long\u2010term pulmonary vasodilator therapy, and 9 (43%) received concurrent calcium\u2010channel blockers. Treatment\u2010na\u00efve children (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200912) demonstrated stable\/improved functional class with therapy initiation. Median follow\u2010up was 7.1 years (range 0.7\u201317.2). Transplant\u2010 or Potts shunt\u2010free survival at 1 and 5 years was 100% and 94.4% respectively and was worse in the CNV group (Log\u2010rank\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this large pediatric\n                      <jats:italic>TBX4<\/jats:italic>\n                      \u2010PH cohort, children carrying CNVs had greater multisystem involvement and poorer outcomes than those carrying SNVs, highlighting the importance of the underlying genetic finding for risk stratification and tailored management strategies.\n                    <\/jats:p>\n                  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