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Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood
Rachel E Harrison1, Rolf Berger, Sheila G Haworth
1Division of Medical Genetics, University of Leicester, Leicester, UK.
Insights
Genetic mutations in transforming growth factor-beta receptors are a key cause of childhood pulmonary arterial hypertension (PAH). Early-onset PAH, particularly idiopathic PAH, often involves these genetic defects, highlighting a heterogeneous etiology.
Area of Science:
- Pediatric cardiology
- Genetics
- Molecular biology
Background:
- Pulmonary arterial hypertension (PAH) is a severe vascular disease.
- Adult PAH is linked to BMPR2 and ALK-1 gene mutations.
- Childhood PAH can be idiopathic or associated with congenital heart disease.
Purpose of the Study:
- Investigate genetic causes of early-onset PAH in children.
- Analyze mutations in transforming growth factor-beta signaling pathway genes.
- Determine the role of genetic defects in childhood PAH.
Main Methods:
- Mutation analysis of TGF-beta pathway genes in 18 children (<6 years) with PAH.
- Genetic testing for BMPR2, ALK-1, and endoglin.
- Clinical data review for presenting features and disease progression.
Main Results:
- Germ-line mutations found in 22% of children with PAH.
- BMPR2 mutations (11%) included de novo deletion and nonsense mutation.
- ALK-1 and endoglin mutations were also identified in idiopathic PAH cases.
- No clear distinction in clinical features based on mutation status.
Conclusions:
- Childhood PAH has a heterogeneous genetic basis.
- Genetic defects in transforming growth factor-beta receptors are critical in childhood PAH.
- Genetic testing is important for understanding the etiology of early-onset PAH.
Background:
Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic.
Methods And Results:
We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations.
Conclusions:
The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.
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