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Published on: May 11, 2015
Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension
Carrie L Welch1, Wendy K Chung1,2
1Department of Pediatrics, Irving Medical Center, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Insights
Pediatric pulmonary arterial hypertension (PAH) has a distinct genetic basis compared to adults, with a higher burden of rare genetic factors and de novo variants. A genomics-first approach is crucial for better diagnosis and treatment of childhood PAH.
Area of Science:
- Genetics
- Pediatrics
- Cardiology
Background:
- Pulmonary arterial hypertension (PAH) is a rare, high-mortality disease influenced by genetic and environmental factors.
- Pediatric PAH presents unique challenges, including severe clinical courses and developmental anomalies, necessitating distinct research approaches.
- Current pediatric PAH care relies on adult data, overlooking significant differences in etiology and prognosis.
Purpose of the Study:
- To highlight the distinct genetic underpinnings of pediatric-onset PAH compared to adult-onset PAH.
- To emphasize the need for a dedicated pediatric research agenda, including a genomics-first strategy.
- To advocate for improved molecular diagnosis and clinical management tailored to children with PAH.
Main Methods:
- Review of genetic studies focusing on pediatric-onset pulmonary arterial hypertension.
- Comparative analysis of genetic burden and variant types between pediatric and adult PAH cohorts.
- Assessment of current clinical management standards and their limitations for pediatric PAH.
Main Results:
- Rare genetic factors contribute significantly to pediatric PAH (~42%) versus adult PAH (~12.5%).
- De novo variants are prevalent in pediatric PAH, accounting for at least 15% of cases.
- Pediatric PAH exhibits greater etiologic heterogeneity and a poorer prognosis than adult PAH.
Conclusions:
- The genetic architecture of pediatric PAH differs substantially from adult PAH, characterized by a higher genetic burden.
- A genomics-first approach is essential for advancing the understanding, diagnosis, and treatment of pediatric PAH.
- Developing tailored pediatric research and management strategies is critical to address the unique aspects of childhood PAH.
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.
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