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Published on: May 11, 2015
Genetics and Other Omics in Pediatric Pulmonary Arterial Hypertension
Carrie L Welch1, Wendy K Chung2
1Department of Pediatrics, Columbia University Medical Center, New York, NY.
Insights
Pediatric pulmonary arterial hypertension (PAH) has a distinct genetic basis compared to adults, with developmental genes playing a key role. A genetics-first approach can improve risk stratification and treatment for children with this rare disease.
Area of Science:
- Genetics
- Pediatric Cardiology
- Rare Diseases
Background:
- Pulmonary arterial hypertension (PAH) in children presents unique challenges due to complex etiology and limited pediatric data.
- PAH in children often co-occurs with congenital heart disease and developmental disorders.
- Genetic studies reveal a different genetic basis for pediatric-onset PAH compared to adult-onset PAH.
Purpose of the Study:
- To highlight the distinct genetic underpinnings of pediatric-onset PAH.
- To emphasize the need for large cohorts and a genetics-first approach in pediatric PAH research.
- To propose a novel strategy for improved risk stratification and treatment in pediatric PAH.
Main Methods:
- Analysis of genetic studies in pediatric-onset PAH.
- Comparison of genetic factors in pediatric versus adult PAH.
- Identification of key genes contributing to pediatric PAH, including BMPR2 and developmental genes like TBX4 and SOX17.
Main Results:
- Children with idiopathic PAH (IPAH) have a higher genetic burden (≥35%) from rare genetic factors compared to adults (approx. 11%).
- De novo variants are a frequent cause (approx. 15%) of monogenetic PAH in children.
- Rare variants in developmental genes are increasingly recognized as significant contributors to pediatric PAH.
Conclusions:
- The genetic architecture of pediatric PAH differs significantly from adult PAH, with a greater contribution from rare genetic and developmental factors.
- A genetics-first approach, followed by phenotyping based on genetic diagnosis, is proposed to define endophenotypes for better risk stratification and treatment in pediatric PAH.
- Further research with large pediatric PAH cohorts is crucial to fully elucidate unique etiologic differences and guide clinical management.
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.
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