Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene-environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that 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 ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Keywords: genomics; lung disease; pediatrics; pulmonary arterial hypertension.

Figure 1

Relative contributions of de novo mutations and 18 PAH risk genes in a cohort of 443 pediatric and 2628 adult cases from CUIMC and the PAH Biobank. Risk genes include BMPR2, ABCC8, ACVRL1, ATP13A3, BMPR1B, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KDR, NOTCH1, SMAD1, SMAD4, SMAD9, and TBX4. PAH cases include IPAH, APAH, FPAH and other rarer cases.

Figure 2

Age-of-disease onset for all PAH Biobank cases with rare deleterious variants in known PAH risk genes. Box plots showing median, interquartile range and min/max values for age-of-disease onset (i.e., age at diagnostic right heart catheterization). The number of cases carrying variants for each gene is given above each box plot. Genes represented by less than four cases are not shown.

Figure 3

Locations of SOX17 likely gene disrupting (LGD) and rare predicted deleterious missense (D-Mis) variants carried by PAH cases from five cohorts from the US, UK and Japan. Variants carried by pediatric cases (n = 19) are shown above the protein schematic and variants carried by adult cases (n = 13) below the schematic. The combined datasets include 273 pediatric and 3455 adult cases [11,13,22,41,42].

Figure 4

Genomic approach to improve understanding of pediatric PAH.