Genetics and Other Omics in Pediatric Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite therapeutic advances. Clinical management of children with PAH is particularly challenging because of increased complexity of disease etiology and clinical presentation, and the lack of data from pediatric-specific clinical trials. In children, PAH often develops in association with congenital heart disease and other developmental disorders. Emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis 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 approximately 11% of adult-onset IPAH. De novo variants are the most frequent monogenetic cause of PAH in children, likely contributing to approximately 15% of all cases. Rare deleterious variants in BMPR2 contribute to pediatric-onset IPAH and familial PAH with similar frequency as adult-onset disease but rarely explain cases of PAH associated with other diseases. Rare deleterious variants in developmental genes-including TBX4, SOX17, and other genes requiring confirmation in larger cohorts-are emerging as important contributors to pediatric-onset disease. Because each causal gene contributes to only a small number of cases, large cohorts of pediatric-onset PAH are needed to further identify the unique etiologic differences of PAH in children. We propose a genetics-first approach followed by focused phenotyping of pediatric patients grouped by genetic diagnosis to define endophenotypes that can be used to improve risk stratification and treatment.

Keywords: genomics; lung disease; pediatrics.