Genes that drive the pathobiology of pediatric pulmonary arterial hypertension

Emerging data from studies of pediatric‐onset pulmonary arterial hypertension (PAH) indicate that the genomics of pediatric PAH is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 35% of pediatric‐onset idiopathic PAH (IPAH) compared with ~11% of adult‐onset IPAH. De novo variants are the most frequent genetic cause of PAH in children, likely contributing to ~15% of all cases. Rare deleterious variants in bone morphogenetic protein receptor 2 (BMPR2) contribute to pediatric‐onset familial PAH and IPAH with similar frequency as adult‐onset. While likely gene‐disrupting (LGD) variants in BMPR2 contribute across the lifespan, damaging missense variants are more frequent in early‐onset PAH. Rare deleterious variants in T‐box 4‐containing protein (TBX4) are more common in pediatric‐compared with adult‐onset PAH, explaining ~8% of pediatric IPAH. PAH associated with congenital heart disease (APAH‐CHD) and other developmental disorders account for a large proportion of pediatric PAH. SRY‐related HMG box transcription factor (SOX17) was recently identified as an APAH‐CHD risk gene, contributing less frequently to IPAH, with a greater prevalence of rare deleterious variants in children compared with adults. The differences in genetic burden and genes underlying pediatric‐ vs adult‐onset PAH indicate that genetic information relevant to pediatric PAH cannot be extrapolated from adult studies. Large cohorts of pediatric‐onset PAH are necessary to identify the unique etiological differences of PAH in children, as well as the natural history and response to therapy.