Cara Morgan, Laura Southgate, Alistair Calder, Thivya Sekar, Andrew Constantine, Sadia Quyam, Richard Trembath, Shahin Moledina
Great Ormond Street Hospital for Children. University of London, School of Health & Medical Sciences. Queen Elizabeth Hospital Birmingham. University College London. King’s College London.
United Kingdom
International Journal of Cardiology
Int J Cardiol 2025;
DOI: 10.1016/j.ijcard.2025.134114
Abstract
Background: SOX17 has recently been identified as a risk gene for idiopathic/ heritable and co-incidental congenital heart disease (CHD) pulmonary arterial hypertension (PAH). Distinct phenotypic characteristics in PAH associated with variants in SOX17 (SOX17-PAH) are still emerging.
Methods: Retrospective review describing natural history and outcomes in a national cohort of children with SOX17-PAH. Findings were collated with data from previously reported individuals to compare adult and paediatric cases.
Results: In the current cohort 8/69 (11.6 %) children tested had a variant and 6 variants are newly reported. Six children had CHD. Haemodynamic assessment demonstrated high mean pulmonary artery pressure (60 [49-102] mmHg) and pulmonary vascular resistance (17.2 [9.6-27.7] WU.m2). Atypical radiological features included ground-glass opacification and pulmonary arterial tortuosity. Despite combination-therapy, outcomes were poor (lung transplant/death = 5) with median transplant/Potts-shunt-free survival of 7.5 [0.1-15.1] years. In addition to the present cohort, published phenotypic data were available in 71 individuals. Combining data across studies showed a bimodal distribution of age at disease onset, with majority having childhood-onset PAH (69 %). Those with CHD were diagnosed younger (8.8 versus 21.7 years, p < 0.001). Variants located in the HMG-box domain were more likely to have childhood-onset PAH (52.6 % versus 20.7 %, p = 0.005). Where reported, 26 % of paediatric cases underwent Potts-shunt and 38 % of all cases underwent lung transplantation.
Conclusion: This study suggests SOX17-PAH is characterised by unfavourable haemodynamics, high rates of CHD and treatment-refractory disease. The location of SOX17 variants may influence the age of onset of PAH.
Category
Class I. Heritable Pulmonary Hypertension
Genetic Factors Associated with Pulmonary Vascular Disease
Symptoms and Findings Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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Free PDF File or Full Text Article Available Through PubMed or DOI: Yes