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.