Abstract
Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance.
Highlights
Pulmonary arterial hypertension (PAH) is an uncommon vascular disorder that remains incurable despite significant advances in current treatment regimens
All variants were validated by Sanger sequencing
Based on our exclusion criteria, no other likely causal variants in the reported PAH risk genes were identified in these patients
Summary
Pulmonary arterial hypertension (PAH) is an uncommon vascular disorder that remains incurable despite significant advances in current treatment regimens. Typical histopathological features of PAH include marked vascular remodelling of the pulmonary arterioles as a consequence of exuberant proliferation of pulmonary artery endothelial (PAEC) and smooth muscle (PASMC). Despite major advances in delineating PAH aetiology, the associated morbidity and early mortality burden of this disease remains perniciously high, with an average life expectancy of 3–5 years from diagnosis [3]. At an estimated 4.8–8.1 cases/million [4,5], than the adult form (15–50 cases/million) [6], childhood-onset PAH (cPAH) is marked by greater morbidity, depressed responses to therapy and poor survival metrics [7,8]
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