Variant Class-Specific Phenotypes and Outcomes in Pediatric TBX4-Associated Pulmonary Hypertension

To describe the variant class associations with phenotype, natural history, treatment response, and outcomes in children with TBX4-associated pulmonary hypertension (TBX4-PH).

Retrospective cohort analysis of children < 18 years referred to the National Paediatric Pulmonary Hypertension Service between 2001 and 2025.

Twenty-one children were identified carrying either a copy number variant (CNV group = 10) encompassing TBX4 or a single nucleotide variant (SNV group = 11). Distinct phenotypic differences were observed between variant classes. Children in the CNV group were referred at a younger age (p = 0.03), more frequently had prolonged oxygen dependence from birth (p < 0.01), more severe lung disease (p < 0.01) and cyanosis (p = 0.04), congenital heart disease (p = 0.03), neurodevelopmental disorders (p < 0.01), and deafness (p = 0.01). Children in the SNV group were less likely to have any lung disease (p = 0.03). Histopathology from five children (CNV = 3, SNV = 2) demonstrated predominantly lung growth abnormalities with variable pulmonary vascular remodeling. Twenty of 21 (95%) children received long-term pulmonary vasodilator therapy, and 9 (43%) received concurrent calcium-channel blockers. Treatment-naïve children (n = 12) demonstrated stable/improved functional class with therapy initiation. Median follow-up was 7.1 years (range 0.7-17.2). Transplant- or Potts shunt-free survival at 1 and 5 years was 100% and 94.4% respectively and was worse in the CNV group (Log-rank p < 0.05).

In this large pediatric TBX4-PH 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.